ANNUAL REVIEWS
Further
Quick links to online content Annu. Rev. Physiol. 1990.52:275-92 Copyright © 1990 by Annual Reviews Inc. All rights reserved
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
ROLE OF G PROTEINS IN CALCIUM CHANNEL MODULATION G. Schultz, W. Rosenthal, and J. Hescheler Institut fur Phannakologie, Freie Universitat Berlin, Thielallee 69173, D-IOOO Berlin 33, West Germany
W. Trautwein Physiologisches Institut, Universitat des Saarlandes, D-6650 Homburg/Saar, West Germany KEY WORDS:
signal transduction, Ca2+ influx, ion channels, pertussis toxin, guanine nucleotides
INTRODUCTION Modulation of Ca2+ -penneable ion channels by honnones and neurotransmit ters is accomplished by reversibly interacting signal transduction components of the plasma membrane and the cytosol. The first component of the signal transduction chain is a transmembranous receptor that binds extracellular signal molecules with high specificity. Typically, the receptors are glycosyl ated monomers with an amino acid sequence predictive for seven membrane spanning regions (57). Following the binding of an agonist, receptors interact with and thereby activate heterotrimeric (a{3'Y) guanine nucleotide-binding proteins (G proteins) attached to the inner face of the plasma membrane (Brown & Bimbaumer, this volume). Activation of G proteins leads to an exchange of GDP for GTP bound to their a-subunit. GTP-liganded a-subunits affect the activity of effectors that generate intracellular signals. In the case of the ubiquitous cAMP-generating enzyme, the adenylate cyclase, and the retinal light-sensitive cGMP-phosphodiesterase activity changes result from 275
0066-4278/90/0315-0275$02.00
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
276
SCHULTZ ET AL
direct interactions with G protein a-subunits, as was shown in reconstitution experiments with purified components (17, 28). A direct interaction of G protein subunits with ion channels has not been demonstrated. However evidence is increasing that receptor-activated G proteins can affect the activity of ion channels by membrane-confined mechanisms. The best studied example for a close control of ion channels by G proteins is cardiac K+ channels. In excised membrane patches of guinea pig atrial cells, activated G protein a-subunits of the Gi family, (GiI-3), purified from human erythrocytes or bovine brain are sufficient to stimulate K+ channels if applied to the cytoplasmic face of the patch at subpicomolar concentrations (101); recombinant Gi a-subunits are also active. Surprisingly, G protein ,By-complexes have also been reported to activate atrial K+ channels in membrane patches; the stimulatory effect is observed at relatively high (nM) concentrations and apparently requires metabolites of arachidonic acid (52; see also Szabo this volume). In addition, the a-subunit of the G protein, Gk (representing a mixture of Gi2 and Gi3) stimulates K+ channels in isolated membrane patches of a pituitary cell line, GH3, if applied at subpicomolar concentrations (11). Moreover the G protein, Go, isolated from bovine brain activates a variety of otherwise quiescent K+ channels in cell-free membrane patches of neuronal cells if employed at a concentration of 1 pM (92); the ability is retained in a recombinant Go a-subunit. A close control by G-proteins also appears to apply to voltage-dependent Ca2+ channels. The main purpose of this contribution is to review data suggesting that G proteins exert both a membrane-confined stimulatory and a membrane-confined inhibitory control of voltage-dependent Ca2+ channels. We also discuss other G protein involving mechanisms by which receptor agonists modulate Ca2+ influx through ion channels. CLOSE CONTROL OF VOLTAGE-DEPENDENT Ca2+ CHANNELS BY G PROTEINS Inhibition of Voltage-Dependent Ca2+ Channels in Neuronal and Endocrine Cells In neuronal cells of vertebrates the inhibition of voltage-dependent Ca2+ channels by receptor agonists provides a molecular mechanism for the inhibition of neurosecre tion via presynaptic receptors. In endocrine cells the inhibition of Ca2+ cur rents by receptor agonists may represent a molecular mechanism for the in hibition of secretion. In most studies investigators used the patch-clamp technique (whole-cell recording; 37) to study the inhibitory modulation of Ca2+ currents.
INVOLVED RECEPTOR AGONIST AND CELL TYPES
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
G
PROTEINS AND Ca2+ CHANNELS
277
In dorsal root ganglion cells of chick, Ca2+ currents are inhibited by noradrenaline (via aradrenoceptors), y-aminobutyric acid (GABA, via GABAs-receptors), serotonin and dopamine (via Drreceptors) (14, 22, 311, 43, 63). In dorsal root ganglion neurons of rat, 2-chloroadenosine (via AI-receptors), baclofen (via GABAB-receptors), neuropeptide Y and opioid peptides (via fL-receptors) reduce Ca2+ currents (18, 20, 26, 34, 82, 83), and in dorsal root ganglion neurons of mouse, baclofen and opioid peptides (via K-receptors) decrease Ca2+ currents (352). In sympathetic ganglion neurons of chick, noradrenaline and dopamine inhibit Ca2+ currents (63); in the same cell type of rat, acetylcholine (via muscarinic receptors) induces Ca2+ current inhibition (97). Acetylcholine also inhibits voltage-dependent Ca2+ currents in hippocampal neurons of rat (89). Finally, in mouse/rat neuroblastoma x glioma hybrid cells (108CCI5), opioid peptides (via S-receptors) and soma tostatin reduce Ca2+ currents (40, 91). The extent of Ca2+ current inhibition at maximally effective concentrations of neurotransmitters ranges from 30% (mouse dorsal root ganglion neurons, 35; rat sympathetic ganglion neurons, 97), 40% (rat hippocampal neurons, 89), 60% (rat dorsal root ganglion neurons, 18) to 70% (neuroblastoma x glioma hybrid cells, 40, 91). In pituitary cell lines from mouse (AtT-20) and rat (GH3), somatostatin, a secretion-inhibiting hormone, inhibits voltage-dependent Ca2+ channels by about 34 and 50%, respectively (58, 80). In both neuronal and pituitary cells the inhibitory modulation of Ca2+ currents occurs fast (within seconds) and is rapidly reversed by removal of the receptor agonist (35, 40, 43, 58, 80, 83, 89, 91, 97). EFFECTS OF GUANINE NUCLEOTIDES The agonists mentioned above are known to activate transmembranous receptors coupled to G proteins. The involvement of G proteins in the inhibitory Ca2+ current modulation is evident from the effects of intracellularly applied analogs of guanine nucleo tides. Intracellular application of high concentrations (100 to SOD fLM) of the GTP analog, guanosine-5' -0-(3-thiotriphosphate) (GTPyS), an activator of G proteins, reduces Ca2+ currents in neuronal (40, 43, 83, 89, 97) and pituitary cells (58). GTPyS applied intracellularly at a low concentration (1 fLM) has no effect on Ca2+ currents of neuroblastoma x glioma hybrid cells in the absence of a receptor agonist, but renders irreversible the inhibition caused by a S-receptor agonist (41). Similarly, somatostatin causes an irreversible in hibition of Ca2+ currents in AtT-20 cells infused with a GTPyS-containing solution (58). Using caged GTPrS, which is released by light, Dolphin & coworkers showed that the maximum of Ca2+ current inhibition induced by
'In this study currents through single channels of a cell-attached membrane patch were measured. 2Currents were measured by the use of microelectrodes instead of patch-pipettes.
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
278
SCHULTZ ET AL
moderate concentrations of GTPyS (20 ILM) is reached within 5 to 10 min (21). This rather slow time course of GTPyS action on Ca2+ currents, also described for AtT-20 cells (58), corresponds well to the slow activation of G proteins by GTP analogs in the absence of receptor agonists (Brown & Bimbaumer, this volume). Intracellular application of the GDP analog, guanosine-5' -0-(2-thiodiphos phate) (GDPI3S), which prevents receptor-induced activation of G proteins, also prevents the inhibition of Ca2+ currents by receptor agonists (40,41,43, 83, 97). Activation of G proteins specifically requires GTP. However in almost all studies mentioned above, patch-pipettes were filled with solutions containing ATP but not GTP. Only in few studies (89, 97) pipette solutions contained both ATP and GTP. The apparent ability of ATP to substitute for GTP may be explained by the action of hormone-sensitive, G protein-associated nucleoside diphosphokinases that convert ATP to GTP, thus providing the nucleotide required for G protein activation (53,75,84). There is no easy explanation for the fact that some investigators observe receptor-mediated Ca2+ channel inhibition when infusing nucleotide-free solutions into cells (63, 91). Since under these experimental conditions reversible inhibition of Ca2+ currents is observed up to 20-30 min after achievement of the whole-cell configur ation (63), one has to assume that a sufficient concentration of GTP is main tained at the inner face of the plasma membrane, either by permanent syn thesis of nucleotides, tight binding of nucleotides to the plasma membrane, or by the existence of compartments that are not easily accessible to the pipette solution. SENSITIVITY TOWARDS PERTUSSIS TOXIN The main exotoxin of Bor detella pertussis, pertussis toxin, prevents coupling of activated receptors to some G proteins (e.g. members of the Gi family and Go) by ADP-ribosylation of G protein a-subunits (Brown & Bimbaumer,this volume). Treatment with pertussis toxin for several hours prevented the agonist-induced inhibition of Ca2+ currents in dorsal root ganglion neurons (86), AtT-20 cells (58),neuro blastoma x glioma hybrid cells (40), GH3 cells (80), and hippocampal neurons (89). Analogous to data obtained with regard to inhibition of adeny late cyclase,GTPyS-induced inhibition of Ca2+ currents in neuroblastoma x glioma hybrid cells was not abolished by pertussis toxin (41). POSSIBLE
ROLE OF INTRACELLULAR
SIGNAL MOLECULES OR
PROTEIN
Agonists that inhibit Ca2+ currents also inhibit adenylate cyclase KINASES thereby reducing cytosolic cAMP levels (e.g. adrenaline via ll'2-adrenocep tors, GABA via GABAB-receptors, dopamine via D2-receptors, opioids via 8-, IL- and K-receptors, adenosine via Arreceptors) (49). Inhibition of both Ca2+ channels and adenylate cyclase are mediated by pertussis
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
G PROTEINS AND Ca2+ CHANNELS
279
toxin-sensitive G proteins. However in contrast to the hormonal modulation of cardiac Ca2+ channels (Trautwein & Hescheler this volume), cAMP or cAMP-dependent protein kinase are not involved in the receptor-mediated inhibition of Ca2+ currents in neuronal and pituitary cells for several reasons. (a) Intracellular infusion of cAMP in the absence of a hormonal agonist does not affect Ca2+ channel activity (40, 80, 97). (b) Agonists inhibit Ca2+ currents in cells loaded with cAMP (43, 58, 97). (c) Extracellular application of the adenylate cyclase-stimulating diterpene, forskolin, does not modify Ca2+ currents in neuroblastoma x glioma hybrid cells (41), or GH3 cells (80), nor does it prevent the inhibition of Ca2+ currents by a GABAB receptor agonist in rat dorsal root ganglion neurons (19). For effects of cAMP on neuronal L-type Ca2+ currents see chapter by Dolphin, this volume. Based on data obtained with modulators of protein kinase C, both a stimulatory and an inhibitory control of neuronal and pituitary Ca2+ currents by protein kinase C have been suggested (Dolphin, this volume; 62, 863). The inhibitory effects led to the hypothesis that protein kinase C is involved in the receptor-mediated inhibition of Ca2+ currents (78). This assumption, howev er, appears to be unlikely for several reasons. (a) The main activator of protein kinase C, diacylglycerol, is formed by phosphoinositide hydrolysis catalyzed by a phospholipase C (6). However most receptor agonists that inhibit Ca2+ currents in neuronal and pituitary cells do not stimulate phos phoinositide hydrolysis; consequently, they do not activate protein kinase C via this pathway. (b) In contrast to Ca2+ current inhibition, the receptor mediated phosphoinositide hydrolysis in pituitary cells is not blocked by pertussis toxin (64, 69, for review see Reference 27). (c) Activators and inhibitors of protein kinase C do not affect the agonist-induced inhibition of Ca2+ currents in rat sympathetic ganglion neurons (97) and in chick dorsal root ganglion neurons (51). (el) Bradykinin, which stimulates phospholipase C in both cell types, does not inhibit voltage-dependent Ca2+ channels in neuroblastoma x glioma hybrid cells (G. Schultz et ai,unpublished), or in rat dorsal root ganglion cells (19). In addition, there is convincing evidence that in neuroblastoma x glioma hybrid neurons, bradykinin-induced phosphoinosi tide hydrolysis is insensitive to pertussis toxin (33, 74), although there is a contradictory report (42). Also opposed to the findings described above is a report by Ewald et al (25); according to this group, bradykinin inhibits voltage-dependent Ca2+ currents of rat dorsal root ganglion neurons in a pertussis toxin-sensitive manner; however in this study the possible involve ment of protein kinase C has not been examined. Fatty acids, in particular arachidonic acid, also activate protein kinase C (85). Arachidonic acid is formed following the activation of phospholipase A 2 3Ca2+ influx was determined by the use of the fluorescent Ca2+ chelator, fura-2.
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
280
SCHULTZ ET AL
or-subsequent to phosphoinositide hydrolysis-by a diacylglycerol lipase. At least in some cell types, receptor-mediated stimulation of a phospholipase A is sensitive to pertussis toxin (for review see Reference 27). However 2 arachidonic acid or an inhibitor of phospholipases does not affect Ca2+ currents in chick (51) or rat dorsal root ganglion neurons (19). Arachidonic acid may also affect Ca2+ channel activity by stimulation of a cGMP-generating enzyme, i.e. soluble guanylate cyclase, and subsequent activation of cGMP-dependent protein kinase (32). In contrast to snail neurons (76), this pathway is apparently not involved in the inhibition of Ca2+ currents in neuronal cells of vertebrates, since cGMP, applied intracellularly, does not affect Ca2+ currents in neuroblastoma x glioma hybrid cells (G. Schultz et aI, unpublished observation), nor does nitroprusside, a potent stimulator of soluble guanylate cyclase, affect Ca2+ currents in chick dorsal root ganglion neurons (51). Thus a role of a phospholipase A in the in 2 hibitory modulation of neuronal Ca2+ channels appears unlikely. In pituitary cells a possible involvement of phospholipase A in the receptor-induced 2 Ca2+ channel inhibition has not yet been investigated. In conclusion, intracellular signal molecules or protein kinases stimulated by intracellular signal molecules are apparently not involved in the pertussis toxin-sensitive inhibitory Ca2+ current modulation. A membrane-confined mechanism is also supported by experiments in which currents through single Ca2+ channels of a cell-attached patch (37) were recorded. In this configura tion, the membrane under the tip of the pipette is not accessible for agonists applied to the bath solution. In chick and mouse dorsal root ganglion cells (31, 34), application of inhibitory agonists to the bath solution does not induce an inhibition of Ca2+ channels in the patch, which suggests that readily diffusible intracellular signal molecules are not involved in the in hibitory modulation of Ca2+ currents (see also Dolphin, this volume). ca2+ CHAN The G protein that physiologically mediates pertussis toxin-sensitive inhibition of voltage-dependent Ca2+ channels in neuronal and endocrine cells has not been identified with certainty. There is, however, some experimental evidence suggesting that the G protein, Go, may be involved. (a) Go is an abundant G protein in cell types that exhibit pertussis toxin-sensitive inhibition of Ca2+ currents, i.e. neuronal cells (2), neuroblast oma x glioma hybrid cells (67), rat pituitary cells (2), and GH3 cells (80). (b) Following the treatment of cells with pertussis toxin, intracellular application of Go or its a-subunit efficiently restores the ability of agonists to inhibit Ca2+ currents in neuroblastoma x glioma hybrid cells (40), rat dorsal root ganglion neurons (26), snail neurons (38), and rat hippocampal neurons (60). (c) Antibodies against the Go a-subunit attenuate the inhibitory modulation of
IDENTITY OF THE G PROTEINS INVOLVED IN THE INHIBITORY NEL MODULATION
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
G
PROTEINS AND Ca2+ CHANNELS
281
Ca2+ currents in snail neurons (38) and in neuroblastoma x glioma hybrid cells (8). (d) The expression of the Go a-subunit in rat pituitary tumor cells correlates with the ability of dopamine to inhibit prolactin secretion (13). (e) Inhibitory agonists efficiently stimulate guanine nucleotide-binding to a 39-kd membrane protein presumably representing N, the Go a-subunit in neuro blastoma x glioma hybrid cells and GH3 cells (S. Offermanns, G. Schultz, & W. Rosenthal, unpublished). According to Attali & coworkers (3), Gil is involved in the inhibition of Ca2+ currents induced by K-receptor agonists. They found that chronic expo sure of rat spinal cord-dorsal root ganglion cocultures to K-receptor agonists attenuates the receptor-mediated inhibition of 45Ca2+ uptake and down reg ulates the Gil a-subunit, but not the Go a-subunit. Based on electro TYPES OF ca2 + CHANNELS INHIBITED BY G PROTEINS physiological and pharmacological properties, neuronal voltage-dependent Ca2+ channels have been classified as L-, N-, and T-type channels (90). Inhibitory neurotransmitters acting via pertussis toxin-sensitive G proteins mainly appear to affect Ca2+ channels of the N- and the T-type (Dolphin this volume). Since N-type channels play a dominant role in neurosecretion (90), the inhibition of N-type channels by neurotransmitters may be relevant for the inhibition of neurosecretion via presynaptic receptors. Isolated and clonal cells from the anterior pituitary possess fast and slowly inactivating Ca2+ currents that apparently correspond to Ca2+ fluxes through L- and T-type channels (e.g. 15,62,80). GH3 cells may,in addition,possess slowly inactivating N-type Ca2+ channels (88). In GH3 cells, somatostatin exclusively inhibits slowly inactivating Ca2+ currents (80). Whether these currents represent currents through L- or N-type channels is not known. Evidence for a control of neuronal and pituitary L-type Ca2+ channels by pertussis toxin-sensitive G proteins is based on experiments with Ca2+ channel-blocking and -activating ligands (Dolphin, this volume, 81). 2+ Stimulation of Voltage-Dependent Ca Channels in Endocrine Cells and in Myocytes of the Heart and Skeletal Muscle
Data reviewed here were obtained by applying the patch-clamp technique in the whole-cell configuration (37). In bovine adrenal glomerulosa cells (12), as well as in the adrenocortical cell line, Yl (39), angiotensin II, the major stimulator of aldosterone secretion, stimulates vol tage-dependent Ca2+ currents up to about 1.7-fold. According to preliminary data, angiotensin II is also active in isolated porcine (39) and in pituitary GH3 cells (80). In Yl cells, stimulation is observed a few seconds after addition of the hormone and is rapidly reversed b)' its removal from the bath (39). ENDOCRINE CELLS
282
SCHULTZ ET AL
Similarly to angiotensin II, the secretion-stimulating hormone, luteinizing hormone-releasing
hormone
(gonadotropin-releasing
hormone,
GnRH,
LHRH), stimulates voltage-dependent Ca2+ currents of GH3 cells about 1.5-fold in a rapid and reversible fashion (80). Thus in this cell type, receptor agonists exert a dual control of voltage-dependent Ca2+ currents (see above).
Effects of pertussis toxin
Stimulation of Ca2+ currents in Y I cells is abol
ished by treatment of cells with pertussis toxin (39). This observation con
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
firms a previous finding that pertussis toxin abolishes the stimulation of 45Ca2+ influx by angiotensin II (54). In pituitary GH3 cells, pertussis toxin not only abolishes the inhibitory but also the stimulatory Ca2+ current modulation (80). Consistent with this observation is the finding that both stimulatory and inhibitory hormones stimulate high-affinity GTPases in membranes from GH3 cells (representing the enzymatic activity of G proteins ) and that this effect is sensitive to pertussis toxin (72). Thus in GH3 cells both stimulatory and inhibitory hormones apparently modulate Ca2+ channels via pertussis toxin-sensitive G proteins.
Independency of cAMP
While Ca2+
currents in cardiac and skeletal
myocytes are stimulated by cAMP-dependent phosphorylation (Trautwein & Hescheler, this volume), the stimulatory modulation of Ca2+ currents in adrenocortical and pituitary cells appears to be independent of cAMP for several reasons. (a) Intracellularly applied cAMP or extracellularly applied forskolin does not stimulate Ca2+ currents in Y l or GH3 cells (39, 80). (b) In
membranes of adrenocortical and pituitary cells, angiotensin II does not stimulate but rather inhibits adenylate cyclase (23, 80, 98). (c) LHRH does not affect adenylate cyclase activity in membranes of GH3 cells (80). (d) The sensitivity of the stimulatory Ca2+ current modulation towards pertussis toxin further indicates that elevation of cAMP is not an intermediate step since
stimulation of adenylate cyclase is mediated by G., a G protein that is a substrate for cholera toxin but not for pertussis toxin (Brown & Birnbaumer, this volume).
Possible involvement of phospholipases
In adrenocortical
(24, 54) and
pituitary cells (64, 69), angiotensin II, LHRH, and thyrotropin-releasing
hormone (TRH) stimulate a phospholipase C and, thereby, phosphoinositide hydrolysis via pertussis toxin-insensitive mechanisms. It is, therefore, un likely that activation of protein kinase C or mobilization of intracellularly stored Ca2+ via this pathway is involved in the Ca2+ current stimulation by angiotensin II and LHRH'
Another possible mechanism underlying the agonist-induced Ca2+ current
G PROTEINS AND Ca2+ CHANNELS
283
stimulation is the liberation of arachidonic acid by receptor-mediated, per tussis toxin-sensitive activation of a phospholipase A (see above). In Yl 2 cells, a protein kinase C-activating phorbol ester did not affect Ca2+ currents nor did cGMP affect the Ca2+ current stimulation by angiotensin n
(39). It
remains to be determined whether or not either of these pathways activated by arachidonic acid provides a mechanism for the stimulatory control of Ca2+ currents in pituitary cells. In both adrenocortical and pituitary cells the direct effect of arachidonic acid or its metabolites on Ca2+ channel activity has not
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
been examined. While the data reviewed above are consistent with a membrane-confined mechanism, other investigators suggest that cytosolic components are re quired for the stirilUlatory Ca2+ current modulation in pituitary cells. Taking advantage of the cell-attached variation of the patch-clamp technique, Mason
& Waring (65) found that cation channels permeable to Ca2+ are stimulated by LHRH applied to the bath solution, which therefore suggested the involve ment of a cytosolic messenger. It is however, not clear, whether the cation channels activated by LHRH represent classical voltage-dependent Ca2+ channels. Measuring cytosolic Ca2+ with a fluorescent Ca2+ chelator, Shan gold
& colleagues (86) showed that a protein kinase C-activating phorbol
ester promotes the portion of the LHRH-induced increase in cytosolic Ca2+, which apparently depends on nitrendipine-sensitive Ca2+ influx. Pertussis toxin was not applied in either of these studies.
Identity of the G protein involved in the pertussis toxin-sensitive stimulatory ccl+ channel modulation Data from reconstitution experiments with puri fied G proteins are still missing. Since only two groups of pertussis toxin sensitive G proteins are known in nonretinal tissues (i.e.
OJ and Go), and since
Go apparently mediates inhibition of Ca2+ currents, it appears plausible that a
Gj-type G protein is involved in the pertussis toxin-sensitive stimulation of voltage-dependent Ca2+ channels. This hypothesis is supported by the finding that membranes of Yl cells contain G proteins of the Gj-type, but are devoid of Go
(39). The hypothesis is also consistent with the finding that membranes
of GH3 cells possess-besides large amounts of Go-at least two Gj-type G proteins (80). CARDIAC AND SKELETAL MYOCYTES
The cholera toxin-sensitive G pro
tein, Gs. confers hormonal activation to adenylate cyclase. This leads to stimulation of cAMP-dependent protein kinase, which, in tum, activates cardiac Ca2+ channels (Trautwein
& Hescheler, this volume). Similarly.
cAMP-dependent protein kinase phosphorylates and, thereby. activates the L-type Ca2+ channel purified from T tubules of skeletal muscle (30). Recent evi in the inhibitory regulation of neuronal calcium channels. Adv. 2nd Messenger Phosphoprotein Res. 2 1 :
1 65-74
42. Higashida, H . , Streaty, R. A . , Klee, W . , Nirenberg , M. 1986. Bradykinin activated transmembrane signals are coupled via No or Ni to production of inositol 1 ,4,5-trisphosphate, a second messen ger in NGI08-1S neuroblastoma glioma hybrid cells. Proc. Natl. Acad. Sci. USA 83:942-46 43 . Holz, G. G. IV, Ranc, S. G . , Dunlap, K. 1986. GTP-binding proteins mediate transmitter inhibition of voltage dependent calcium channels. Nature 3 1 9:67�72 44. Hughes, B. P . , Crofts, J. N . , Auld, A . M . , Read, L. C. , Barritt, G. 1987. Evi dence that a pertussis toxin-sensitive substrate is involved in the stimulation by epidermal growth factor and vaso pressin of plasma-membrane Ca2+ in flow in hepatocytes. Biochem. 1. 248:91 1-18 45. Imoto, Y . , Yatani, A., Reeves, J . P., Codina, J., Bimbaumer, L . , Brown, A . M . 1 988. a-subunit o f Gs directly acti vates cardiac calcium channels in lipid bilayers. Am. J. Physiol. 255:H72228 46. Inoue, K . , Kenimer, J. 1988. Muscarin ic stimulation of calcium influx and nor epinephrine release in PC1 2 cells. J. Bioi. Chem. 263:81 57-61 47. Inoue, R . , Isenberg, G. 1989. Receptor operated currents in ileal smooth muscle cells: G�proteins involved in transduc tion for muscarinic acetylcholine recep-
tors to non-specific cation channels. J. Physiol. In press 48. Irvine, R. F . , Moor, R. M. 1987. Inosi tol ( l , 3 ,4,5) tetrakisphosphatc-induced activation of sea urchin eggs requires the presence of inositol trisphosphate. Biochem. Biophys. Res. Commun. 1 46:284-90 49. Jakobs, K. H. , Aktories, K . , Minuth, M . , Schultz, G. 1985. Inhibition of adenylate cyclase. Adv. Cycl. Nucleo tide Protein Phosphorylation Res. 1 9: 1 37-50 50. Kaczmarek, L. K. 1988. The regulation of neuronal calcium and phosphoryla tion. Adv. 2nd Messenger Phosphopro tein Res. 22: 1 1 3-38 5 1 . Kasai, H . , Aosaki, T. 1989. Modulation of Ca-channel current by an adenosine analog mediated by a GTP-binding pro tein in chick sensory neurons. Pfliigers Arch. 414: 145-49 52. Kim, D . , Lewis, D. , Graziadei, L . , Neer, E. 1 . , Bar-Sagi, D . , Clapham, D . E. 1 989. G-protein J3y-subunits activate the cardiac muscarinic K + channels via a phospholipase A2. Nature 337:557-60 53. Kimura, N . , Shimada, N. 1 988. Direct interaction between membrane-associat ed nucleoside diphosphate kinase and GTP-binding proteins (G,), and its regu lation by hormones and guanine nuc leotides. Biochem. Biophys. Res. Com mun. 1 5 1 :248-56 54. Kojima, I . , Shibata, H . , Ogata, E. 1 986. Pertussis toxin blocks angiotensin II-induced calcium influx but not inosi tol trisphosphate production in adrenal glomerulosa cell . FEBS Lett. 204:34751 55. Kuno, M . , Gardner, P . 1987. Ion chan nels activated by inositol 1 ,4 ,5trisphosphate in plasma membrane of human T-Iymphocytes. Nature 326:3014 56. Lacerda, A. E. , Rampe, D . , Brown , A . M . 1988. Effects o f protein kinase C activators on cardiac Ca2+ channels. Na ture 335 :249-5 1 57. Lefkowitz, R. 1 . , Caron, M. C. 1988. Adrenergic receptors. 1. Bioi. Chem. 263:4993-96 58. Lewis, D . L . , Weight, F. F . , Luini, A. 1986. A guanine nucleotide-binding pro tein mediates the inhibition of voltage dependent calcium current by somatosta tin in a pituitary cell line. Proc. Natl. Acad. Sci. USA 83:9035-39 59. Light, D . , Ausiello, D . , Stanton, B. 1 989. G-protein regulation of a cation channel in renal ep ithelial c"lls. J. Clin. Invest. 84:352-56 60. Lux, H . , Toselli, M . , Tokutomi, N.
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
G
PROTEINS AND Ca2+ CHANNELS
1 989. Transmitter-modulation of neuro nal Ca channels. Pfliigers Arch. 4 1 3 : R48 (Supp! .) 6 1 . MacDougall, S . L., Grinstein, S., Gel fand, E. W. 1988. Detection of ligand activated conductive Ca2+ channels in human B lymphocytes. Cell 54:229-34 62. Marchetti, c . , Brown, A. M . 1988. Pro tein kinase activator 1 -0Ieyl-2-acetyl-sn glycerol inhibits two types of calcium currents in GH3 cells. Am. J. Physiol. 254:C206-1 O 63. Marchetti, c . , Carbone, E . , Lux, H . D . 1986. Effects o f dopamine and nor adrenaline on Ca channels of cultured sensory and sympathetic neurons of chick. Pfliigers Arch. 406: 1 04-1 1 64. Martin, T. F. J . , BajjaJieh, S. M . , Lucas, D . O . , Kowalchyk, J. A . 1986. Thyrotropin-releasing hormone stimula tion of polyphosphoinositide hydrolysis in GH3 cell membranes is GTP de pendent but insensitive to cholera or per tussis toxin. J. BioI. Chem. 261 : 10 1 4 143 65. Mason, W . , Waring, D. 1986. Patch clamp recordings of single ion channel activation by gonadotropin-releasing hormone in ovine pituitary gonado trophs. Neuroendocrinology 43:20519 66. Mattera, R . , Graziano, M . P. , Yatani, A . , Zhou, Z. , et a!. 1989. Splice vari ants of the G protein Gs activate both adenylyl cyclase and calcium channels. Science 243:804--7 67. Milligan, G . , Gierschik, P. , Spiegel, A . M . , Klee, W . A . 1 986. The GTP binding regulatory proteins of neuroblas toma x glioma, NGI08- 1 5 , and glioma C6, cells. FEBS Lett. 195:225-30 68. Morris, A. P ., Gallacher, D. V . , Irvine, R. F . , Petersen , O. H. 1987. Synergism of inositol trisphosphate and tetrakis phosphate in activating Ca2+ -dependent K+ channels. Nature 330:635--55 69. Naor, Z . , Azrad, A . , Limor, R . , Zakut, H . , Lotan, M. 1986. Gonadotropin releasing hormone activates a rapid Ca2+ -independent phosphodiester hy drolysis of polyphosphoinositides in pituitary gonadotrophs. J. Bioi. Chem. 26 1 : 1 2506-1 2 70. Nelson, M . T . , Standen, N . B . , Brayden, J. E . , Worley, J. F. III. 1988. Noradrenaline contracts arteries by activating voltage-dependent calcium channels. Nature 336:382-85 7 1 . Ng, J . , Fredholm, B. B . , Jondal, M. , Andersson, T. 1988. Regulation of re ceptor-mediated calcium influx across the plasma membrane in a human leukemic T-cell line: evidence of its de-
291
pendence on an initial calcium mobiliza tion from intracellular stores. Biochim. Biophys. Acta 97 1 :207-1 4 72. Offermanns, S . , Schultz, G . , Rosenthal, W. 1 989. Secretion-stimulating and secretion-inhibiting hormones stimulate high-affinity pertussis-toxin-sensitive GTPases in membranes of a pituitary cell line. Eur. J. B iochem . 1 80:283-87 73. Okya, Y., Kitamura, K . , Kuriyama, H . 1987. Modulation o f ionic currents i n smooth muscle walls o f the rabbit in testine by intracellularly perfused ATP and cyclic AMP. Pfliigers Arch. 408: 465-73 74. Osugi, T . , Imaizumi, T . , Mizushima, A . , Uchida, S . , Yoshida, H. 1 987. Role of a protein regulating guanine nucleotide binding in phosphoinositide breakdown and calcium mobilization by bradykinin in neuroblastoma x glioma hybrid NGI08- 1 5 cells: Effects of per tussis toxin and cholera toxin on recep tor-mediated signal transduction. Eur. J. Pharmacol. 1 37:207- 1 8 75. Otero, A. S . , Breitwieser, G . E . , Szabo, G. 1988. Activation of muscarinic potassium currents by ATP-yS in atrial cells. Science 242:443--45 76. Paupardin-Tritsch, D . , Hammond, c., Gerschenfeld, H . M., Nairn, A . C . , Greengard, P. 1 986. cGMP-dependent protein kinase enhances Ca + current and potentiates the serotonin-induced Ca2+ current increase in snail neurons. Nature 323: 8 1 2-1 4 77. Penner, R . , Matthews, G . , Neher, E . 1 988. Regulation o f calcium influx by second messengers in rat mast cells. Na ture 334:499-504 78. Rane, S . G . , Dunlap, K. 1986. Kinase C activator 1 ,2-0Ieoylacetylglycerol atten uates voltage-dependent calcium current in sensory neurons. Proc. Natl. Acad. Sci. USA 8 3:1 84--88 79. Reuter, H. 1983 . Calcium channel mod ulation by neurotransmitters, enzymes and drugs. Nature 30 1 :569-74 80. Rosenthal, W . , Hescheler, J . , Hinsch, K . -D . , Spicher, K . , Trautwein, W. , Schultz, G. 1988. Cyclic AMP independent, dual regulation of voltage dependent Ca2+ currents by LHRH and somatostatin in a pituitary cell line. EMBO J. 7 : 1 627-33 8 1 . Schettini, G . , Meucci, 0 . , Florio, T . , Grimaldi, M . , Landolfi, E. , Magri, G . , Yasumoto, T. 1988. Pertussis toxin pre treatment abolishes dihydropyridine in hibition of calcium flux in the 235-1 pituitary cell line. Biochem. Biophys. Res. Commun. 1 5 1 :361-69
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
292
SCHULTZ ET AL
82. Schroeder, J. E . , Fischbach, P. S . , Mamo, M . , McClesky, E . W . 1989. Mu opioids inhibit calcium channels. Bio phys. J. 55:38a 83. Scott, R . H., Dolphin, A. C. 1986. Regulation of calcium currents by a GTP analogue: potentiation of (-)-bacIofen mediated inhibition. Neurosci. Lett. 69: 59-64 84. Seifert, R . , Rosenthal, W . , Schultz, G . , Wieland, T., Gierschik, P . , Jakobs, K . H. 1988. The role o f nucleoside diphosphate kinase reactions in G pro tein activation of NADPH oxidase by guanine and adenine nucleotides. Eur. J. Biochem. 175:51-55 85. Seifert, R. , Schachtele, C . , Rosenthal , W. , Schultz, G. 1988. Activation of protein kinase C by cis- and trans-fatty acids and its potentiation by di acylglycerol . Biochem. Biophys. Res. Commun. 154:20-26 86. Shangold, G . , Murphy, S . , Miller , R . 1988. Gonadotropin-releasing hormone induced Ca2+ transients in single identi fied gonadotropes require both in tracellular Ca2+ mobilization and Ca2+ influx. Proc. Natl. Acad. Sci. USA 85: 6566--70 87. Snyder, P. M . , Krause, K.-H., Welsh, M. J. 1988. Inositol trisphosphate iso mers, but not inositol 1 ,3,4,5, tetrakisphosphate , induce calcium influx in Xenopus laevis oocytes . J. Bioi. Chem. 263:1 1048-51 88. Suzuki, N . , Yoshioka, T. 1987. Differ ential blocking action of synthetic w conotoxin on components of Ca2+ chan nel current in clonal GH3 cells. Neuro sci. Lett. 75:235-39 89. Toselli, M . , Lux, H. D. 1989. GTP binding proteins mediate acetylcholine inhibition of voltage-dependent calcium channels in hippocampal neurons. Pflug ers Arch. 4 1 3: 3 1 9-21 90. Tsien, R . W., Lipscombe, D., Madison, D. V . , Bl ey , K. R . , Fox, A. P. 1988. MUltiple types of neuronal calcium channels and their selective modulation. Trends Neurosci. 1 l :431-37 9 1 . Tsunoo, A . , Yoshii, M . , Narahashi, T. 1986. Block of calcium channels by en kephalin and somatostatin in neuroblas toma-glioma hybrid NG108-15 cells. Proc. Natl. Acad. Sci. USA 83:9832-36
92. VanDongen, A. M. J. , Codina, J . , 0late, J . , Mattera, R. , Joho, R. , e t al. 1988. Newly identified brain potassium channels gated by the guanine nucleotide binding protein Go. Science 242: 143337 93. Vilven, I . , Coronado, R . 1988. Opening of dihydropyridine calcium channels in skeletal muscle membranes by inositol trisphosphate. Nature 336:587-89 94. Vivaudou, M. B . , Clapp , L. H. , Walsh, J. V. Ir., Singer, J. J. 1988. Regulation of one type of Ca2+ current in smooth muscle cells by diacylglycerol and acetylcholine. FASEB J. 2:2497-504 95. von Tschamer, V . , Prod'hom, B . , Bag gioJini, M . , Reuter, H. 1986. Ion chan nels in human neutrophils activated by a rise in free cytosolic calcium concentra tion. Nature 324:369-72 96. WallnOfer, A . , Cauvin, C. Riiegf , U. 1987. Vasopressin increases 45Ca + in flux in rat aortic smooth muscle cells. Biochem. Biophys. Res. Commun. 148: 273-78 97. Wanke, E . , Ferroni, A . , MalgaroJi, A . , Ambrosini, A . , Pozzan, T . , Meldolesi, J . 1 987. Activation of a muscarinic re ceptor selectively inhibits a rapidly in activated Ca2+ current in rat symphathe tic neurons. Proc. Natl. Acad. Sci. USA 84:43 1 3-17 98. Woodcook E., McLeod, I. 1986. Adenylate cyclase inhibition is not in volved in the adrenal steroidogenic re sponse to angiotensin II. Endocrinology 1 19: 1 697-702 99. Yatani, A . , Brown, A. M. 1989. Time course of Ca2+ current after a concentra tion jump of isoproterenol. Science 245:71-74 100. Yatani, A . , Codina, I . , Imoto, Y . , Reeves, J. P. , Birnbaumer, L. , Brown, A. M. 1 987. A G protein directly reg ulates mammalian cardiac calcium chan nels . Science 238: 1 288--92 1 0 1 . Yatani, A . , Mattera, R . , Codina, J . , Graf, R. , Okabe, K . , et al. 1988. The G protein-gated K + channel is stimulated by three distinct Gja-subunits. Nature 336:680-82 102. Z
Further
Quick links to online content Annu. Rev. Physiol. 1990.52:275-92 Copyright © 1990 by Annual Reviews Inc. All rights reserved
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
ROLE OF G PROTEINS IN CALCIUM CHANNEL MODULATION G. Schultz, W. Rosenthal, and J. Hescheler Institut fur Phannakologie, Freie Universitat Berlin, Thielallee 69173, D-IOOO Berlin 33, West Germany
W. Trautwein Physiologisches Institut, Universitat des Saarlandes, D-6650 Homburg/Saar, West Germany KEY WORDS:
signal transduction, Ca2+ influx, ion channels, pertussis toxin, guanine nucleotides
INTRODUCTION Modulation of Ca2+ -penneable ion channels by honnones and neurotransmit ters is accomplished by reversibly interacting signal transduction components of the plasma membrane and the cytosol. The first component of the signal transduction chain is a transmembranous receptor that binds extracellular signal molecules with high specificity. Typically, the receptors are glycosyl ated monomers with an amino acid sequence predictive for seven membrane spanning regions (57). Following the binding of an agonist, receptors interact with and thereby activate heterotrimeric (a{3'Y) guanine nucleotide-binding proteins (G proteins) attached to the inner face of the plasma membrane (Brown & Bimbaumer, this volume). Activation of G proteins leads to an exchange of GDP for GTP bound to their a-subunit. GTP-liganded a-subunits affect the activity of effectors that generate intracellular signals. In the case of the ubiquitous cAMP-generating enzyme, the adenylate cyclase, and the retinal light-sensitive cGMP-phosphodiesterase activity changes result from 275
0066-4278/90/0315-0275$02.00
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
276
SCHULTZ ET AL
direct interactions with G protein a-subunits, as was shown in reconstitution experiments with purified components (17, 28). A direct interaction of G protein subunits with ion channels has not been demonstrated. However evidence is increasing that receptor-activated G proteins can affect the activity of ion channels by membrane-confined mechanisms. The best studied example for a close control of ion channels by G proteins is cardiac K+ channels. In excised membrane patches of guinea pig atrial cells, activated G protein a-subunits of the Gi family, (GiI-3), purified from human erythrocytes or bovine brain are sufficient to stimulate K+ channels if applied to the cytoplasmic face of the patch at subpicomolar concentrations (101); recombinant Gi a-subunits are also active. Surprisingly, G protein ,By-complexes have also been reported to activate atrial K+ channels in membrane patches; the stimulatory effect is observed at relatively high (nM) concentrations and apparently requires metabolites of arachidonic acid (52; see also Szabo this volume). In addition, the a-subunit of the G protein, Gk (representing a mixture of Gi2 and Gi3) stimulates K+ channels in isolated membrane patches of a pituitary cell line, GH3, if applied at subpicomolar concentrations (11). Moreover the G protein, Go, isolated from bovine brain activates a variety of otherwise quiescent K+ channels in cell-free membrane patches of neuronal cells if employed at a concentration of 1 pM (92); the ability is retained in a recombinant Go a-subunit. A close control by G-proteins also appears to apply to voltage-dependent Ca2+ channels. The main purpose of this contribution is to review data suggesting that G proteins exert both a membrane-confined stimulatory and a membrane-confined inhibitory control of voltage-dependent Ca2+ channels. We also discuss other G protein involving mechanisms by which receptor agonists modulate Ca2+ influx through ion channels. CLOSE CONTROL OF VOLTAGE-DEPENDENT Ca2+ CHANNELS BY G PROTEINS Inhibition of Voltage-Dependent Ca2+ Channels in Neuronal and Endocrine Cells In neuronal cells of vertebrates the inhibition of voltage-dependent Ca2+ channels by receptor agonists provides a molecular mechanism for the inhibition of neurosecre tion via presynaptic receptors. In endocrine cells the inhibition of Ca2+ cur rents by receptor agonists may represent a molecular mechanism for the in hibition of secretion. In most studies investigators used the patch-clamp technique (whole-cell recording; 37) to study the inhibitory modulation of Ca2+ currents.
INVOLVED RECEPTOR AGONIST AND CELL TYPES
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
G
PROTEINS AND Ca2+ CHANNELS
277
In dorsal root ganglion cells of chick, Ca2+ currents are inhibited by noradrenaline (via aradrenoceptors), y-aminobutyric acid (GABA, via GABAs-receptors), serotonin and dopamine (via Drreceptors) (14, 22, 311, 43, 63). In dorsal root ganglion neurons of rat, 2-chloroadenosine (via AI-receptors), baclofen (via GABAB-receptors), neuropeptide Y and opioid peptides (via fL-receptors) reduce Ca2+ currents (18, 20, 26, 34, 82, 83), and in dorsal root ganglion neurons of mouse, baclofen and opioid peptides (via K-receptors) decrease Ca2+ currents (352). In sympathetic ganglion neurons of chick, noradrenaline and dopamine inhibit Ca2+ currents (63); in the same cell type of rat, acetylcholine (via muscarinic receptors) induces Ca2+ current inhibition (97). Acetylcholine also inhibits voltage-dependent Ca2+ currents in hippocampal neurons of rat (89). Finally, in mouse/rat neuroblastoma x glioma hybrid cells (108CCI5), opioid peptides (via S-receptors) and soma tostatin reduce Ca2+ currents (40, 91). The extent of Ca2+ current inhibition at maximally effective concentrations of neurotransmitters ranges from 30% (mouse dorsal root ganglion neurons, 35; rat sympathetic ganglion neurons, 97), 40% (rat hippocampal neurons, 89), 60% (rat dorsal root ganglion neurons, 18) to 70% (neuroblastoma x glioma hybrid cells, 40, 91). In pituitary cell lines from mouse (AtT-20) and rat (GH3), somatostatin, a secretion-inhibiting hormone, inhibits voltage-dependent Ca2+ channels by about 34 and 50%, respectively (58, 80). In both neuronal and pituitary cells the inhibitory modulation of Ca2+ currents occurs fast (within seconds) and is rapidly reversed by removal of the receptor agonist (35, 40, 43, 58, 80, 83, 89, 91, 97). EFFECTS OF GUANINE NUCLEOTIDES The agonists mentioned above are known to activate transmembranous receptors coupled to G proteins. The involvement of G proteins in the inhibitory Ca2+ current modulation is evident from the effects of intracellularly applied analogs of guanine nucleo tides. Intracellular application of high concentrations (100 to SOD fLM) of the GTP analog, guanosine-5' -0-(3-thiotriphosphate) (GTPyS), an activator of G proteins, reduces Ca2+ currents in neuronal (40, 43, 83, 89, 97) and pituitary cells (58). GTPyS applied intracellularly at a low concentration (1 fLM) has no effect on Ca2+ currents of neuroblastoma x glioma hybrid cells in the absence of a receptor agonist, but renders irreversible the inhibition caused by a S-receptor agonist (41). Similarly, somatostatin causes an irreversible in hibition of Ca2+ currents in AtT-20 cells infused with a GTPyS-containing solution (58). Using caged GTPrS, which is released by light, Dolphin & coworkers showed that the maximum of Ca2+ current inhibition induced by
'In this study currents through single channels of a cell-attached membrane patch were measured. 2Currents were measured by the use of microelectrodes instead of patch-pipettes.
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
278
SCHULTZ ET AL
moderate concentrations of GTPyS (20 ILM) is reached within 5 to 10 min (21). This rather slow time course of GTPyS action on Ca2+ currents, also described for AtT-20 cells (58), corresponds well to the slow activation of G proteins by GTP analogs in the absence of receptor agonists (Brown & Bimbaumer, this volume). Intracellular application of the GDP analog, guanosine-5' -0-(2-thiodiphos phate) (GDPI3S), which prevents receptor-induced activation of G proteins, also prevents the inhibition of Ca2+ currents by receptor agonists (40,41,43, 83, 97). Activation of G proteins specifically requires GTP. However in almost all studies mentioned above, patch-pipettes were filled with solutions containing ATP but not GTP. Only in few studies (89, 97) pipette solutions contained both ATP and GTP. The apparent ability of ATP to substitute for GTP may be explained by the action of hormone-sensitive, G protein-associated nucleoside diphosphokinases that convert ATP to GTP, thus providing the nucleotide required for G protein activation (53,75,84). There is no easy explanation for the fact that some investigators observe receptor-mediated Ca2+ channel inhibition when infusing nucleotide-free solutions into cells (63, 91). Since under these experimental conditions reversible inhibition of Ca2+ currents is observed up to 20-30 min after achievement of the whole-cell configur ation (63), one has to assume that a sufficient concentration of GTP is main tained at the inner face of the plasma membrane, either by permanent syn thesis of nucleotides, tight binding of nucleotides to the plasma membrane, or by the existence of compartments that are not easily accessible to the pipette solution. SENSITIVITY TOWARDS PERTUSSIS TOXIN The main exotoxin of Bor detella pertussis, pertussis toxin, prevents coupling of activated receptors to some G proteins (e.g. members of the Gi family and Go) by ADP-ribosylation of G protein a-subunits (Brown & Bimbaumer,this volume). Treatment with pertussis toxin for several hours prevented the agonist-induced inhibition of Ca2+ currents in dorsal root ganglion neurons (86), AtT-20 cells (58),neuro blastoma x glioma hybrid cells (40), GH3 cells (80), and hippocampal neurons (89). Analogous to data obtained with regard to inhibition of adeny late cyclase,GTPyS-induced inhibition of Ca2+ currents in neuroblastoma x glioma hybrid cells was not abolished by pertussis toxin (41). POSSIBLE
ROLE OF INTRACELLULAR
SIGNAL MOLECULES OR
PROTEIN
Agonists that inhibit Ca2+ currents also inhibit adenylate cyclase KINASES thereby reducing cytosolic cAMP levels (e.g. adrenaline via ll'2-adrenocep tors, GABA via GABAB-receptors, dopamine via D2-receptors, opioids via 8-, IL- and K-receptors, adenosine via Arreceptors) (49). Inhibition of both Ca2+ channels and adenylate cyclase are mediated by pertussis
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
G PROTEINS AND Ca2+ CHANNELS
279
toxin-sensitive G proteins. However in contrast to the hormonal modulation of cardiac Ca2+ channels (Trautwein & Hescheler this volume), cAMP or cAMP-dependent protein kinase are not involved in the receptor-mediated inhibition of Ca2+ currents in neuronal and pituitary cells for several reasons. (a) Intracellular infusion of cAMP in the absence of a hormonal agonist does not affect Ca2+ channel activity (40, 80, 97). (b) Agonists inhibit Ca2+ currents in cells loaded with cAMP (43, 58, 97). (c) Extracellular application of the adenylate cyclase-stimulating diterpene, forskolin, does not modify Ca2+ currents in neuroblastoma x glioma hybrid cells (41), or GH3 cells (80), nor does it prevent the inhibition of Ca2+ currents by a GABAB receptor agonist in rat dorsal root ganglion neurons (19). For effects of cAMP on neuronal L-type Ca2+ currents see chapter by Dolphin, this volume. Based on data obtained with modulators of protein kinase C, both a stimulatory and an inhibitory control of neuronal and pituitary Ca2+ currents by protein kinase C have been suggested (Dolphin, this volume; 62, 863). The inhibitory effects led to the hypothesis that protein kinase C is involved in the receptor-mediated inhibition of Ca2+ currents (78). This assumption, howev er, appears to be unlikely for several reasons. (a) The main activator of protein kinase C, diacylglycerol, is formed by phosphoinositide hydrolysis catalyzed by a phospholipase C (6). However most receptor agonists that inhibit Ca2+ currents in neuronal and pituitary cells do not stimulate phos phoinositide hydrolysis; consequently, they do not activate protein kinase C via this pathway. (b) In contrast to Ca2+ current inhibition, the receptor mediated phosphoinositide hydrolysis in pituitary cells is not blocked by pertussis toxin (64, 69, for review see Reference 27). (c) Activators and inhibitors of protein kinase C do not affect the agonist-induced inhibition of Ca2+ currents in rat sympathetic ganglion neurons (97) and in chick dorsal root ganglion neurons (51). (el) Bradykinin, which stimulates phospholipase C in both cell types, does not inhibit voltage-dependent Ca2+ channels in neuroblastoma x glioma hybrid cells (G. Schultz et ai,unpublished), or in rat dorsal root ganglion cells (19). In addition, there is convincing evidence that in neuroblastoma x glioma hybrid neurons, bradykinin-induced phosphoinosi tide hydrolysis is insensitive to pertussis toxin (33, 74), although there is a contradictory report (42). Also opposed to the findings described above is a report by Ewald et al (25); according to this group, bradykinin inhibits voltage-dependent Ca2+ currents of rat dorsal root ganglion neurons in a pertussis toxin-sensitive manner; however in this study the possible involve ment of protein kinase C has not been examined. Fatty acids, in particular arachidonic acid, also activate protein kinase C (85). Arachidonic acid is formed following the activation of phospholipase A 2 3Ca2+ influx was determined by the use of the fluorescent Ca2+ chelator, fura-2.
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
280
SCHULTZ ET AL
or-subsequent to phosphoinositide hydrolysis-by a diacylglycerol lipase. At least in some cell types, receptor-mediated stimulation of a phospholipase A is sensitive to pertussis toxin (for review see Reference 27). However 2 arachidonic acid or an inhibitor of phospholipases does not affect Ca2+ currents in chick (51) or rat dorsal root ganglion neurons (19). Arachidonic acid may also affect Ca2+ channel activity by stimulation of a cGMP-generating enzyme, i.e. soluble guanylate cyclase, and subsequent activation of cGMP-dependent protein kinase (32). In contrast to snail neurons (76), this pathway is apparently not involved in the inhibition of Ca2+ currents in neuronal cells of vertebrates, since cGMP, applied intracellularly, does not affect Ca2+ currents in neuroblastoma x glioma hybrid cells (G. Schultz et aI, unpublished observation), nor does nitroprusside, a potent stimulator of soluble guanylate cyclase, affect Ca2+ currents in chick dorsal root ganglion neurons (51). Thus a role of a phospholipase A in the in 2 hibitory modulation of neuronal Ca2+ channels appears unlikely. In pituitary cells a possible involvement of phospholipase A in the receptor-induced 2 Ca2+ channel inhibition has not yet been investigated. In conclusion, intracellular signal molecules or protein kinases stimulated by intracellular signal molecules are apparently not involved in the pertussis toxin-sensitive inhibitory Ca2+ current modulation. A membrane-confined mechanism is also supported by experiments in which currents through single Ca2+ channels of a cell-attached patch (37) were recorded. In this configura tion, the membrane under the tip of the pipette is not accessible for agonists applied to the bath solution. In chick and mouse dorsal root ganglion cells (31, 34), application of inhibitory agonists to the bath solution does not induce an inhibition of Ca2+ channels in the patch, which suggests that readily diffusible intracellular signal molecules are not involved in the in hibitory modulation of Ca2+ currents (see also Dolphin, this volume). ca2+ CHAN The G protein that physiologically mediates pertussis toxin-sensitive inhibition of voltage-dependent Ca2+ channels in neuronal and endocrine cells has not been identified with certainty. There is, however, some experimental evidence suggesting that the G protein, Go, may be involved. (a) Go is an abundant G protein in cell types that exhibit pertussis toxin-sensitive inhibition of Ca2+ currents, i.e. neuronal cells (2), neuroblast oma x glioma hybrid cells (67), rat pituitary cells (2), and GH3 cells (80). (b) Following the treatment of cells with pertussis toxin, intracellular application of Go or its a-subunit efficiently restores the ability of agonists to inhibit Ca2+ currents in neuroblastoma x glioma hybrid cells (40), rat dorsal root ganglion neurons (26), snail neurons (38), and rat hippocampal neurons (60). (c) Antibodies against the Go a-subunit attenuate the inhibitory modulation of
IDENTITY OF THE G PROTEINS INVOLVED IN THE INHIBITORY NEL MODULATION
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
G
PROTEINS AND Ca2+ CHANNELS
281
Ca2+ currents in snail neurons (38) and in neuroblastoma x glioma hybrid cells (8). (d) The expression of the Go a-subunit in rat pituitary tumor cells correlates with the ability of dopamine to inhibit prolactin secretion (13). (e) Inhibitory agonists efficiently stimulate guanine nucleotide-binding to a 39-kd membrane protein presumably representing N, the Go a-subunit in neuro blastoma x glioma hybrid cells and GH3 cells (S. Offermanns, G. Schultz, & W. Rosenthal, unpublished). According to Attali & coworkers (3), Gil is involved in the inhibition of Ca2+ currents induced by K-receptor agonists. They found that chronic expo sure of rat spinal cord-dorsal root ganglion cocultures to K-receptor agonists attenuates the receptor-mediated inhibition of 45Ca2+ uptake and down reg ulates the Gil a-subunit, but not the Go a-subunit. Based on electro TYPES OF ca2 + CHANNELS INHIBITED BY G PROTEINS physiological and pharmacological properties, neuronal voltage-dependent Ca2+ channels have been classified as L-, N-, and T-type channels (90). Inhibitory neurotransmitters acting via pertussis toxin-sensitive G proteins mainly appear to affect Ca2+ channels of the N- and the T-type (Dolphin this volume). Since N-type channels play a dominant role in neurosecretion (90), the inhibition of N-type channels by neurotransmitters may be relevant for the inhibition of neurosecretion via presynaptic receptors. Isolated and clonal cells from the anterior pituitary possess fast and slowly inactivating Ca2+ currents that apparently correspond to Ca2+ fluxes through L- and T-type channels (e.g. 15,62,80). GH3 cells may,in addition,possess slowly inactivating N-type Ca2+ channels (88). In GH3 cells, somatostatin exclusively inhibits slowly inactivating Ca2+ currents (80). Whether these currents represent currents through L- or N-type channels is not known. Evidence for a control of neuronal and pituitary L-type Ca2+ channels by pertussis toxin-sensitive G proteins is based on experiments with Ca2+ channel-blocking and -activating ligands (Dolphin, this volume, 81). 2+ Stimulation of Voltage-Dependent Ca Channels in Endocrine Cells and in Myocytes of the Heart and Skeletal Muscle
Data reviewed here were obtained by applying the patch-clamp technique in the whole-cell configuration (37). In bovine adrenal glomerulosa cells (12), as well as in the adrenocortical cell line, Yl (39), angiotensin II, the major stimulator of aldosterone secretion, stimulates vol tage-dependent Ca2+ currents up to about 1.7-fold. According to preliminary data, angiotensin II is also active in isolated porcine (39) and in pituitary GH3 cells (80). In Yl cells, stimulation is observed a few seconds after addition of the hormone and is rapidly reversed b)' its removal from the bath (39). ENDOCRINE CELLS
282
SCHULTZ ET AL
Similarly to angiotensin II, the secretion-stimulating hormone, luteinizing hormone-releasing
hormone
(gonadotropin-releasing
hormone,
GnRH,
LHRH), stimulates voltage-dependent Ca2+ currents of GH3 cells about 1.5-fold in a rapid and reversible fashion (80). Thus in this cell type, receptor agonists exert a dual control of voltage-dependent Ca2+ currents (see above).
Effects of pertussis toxin
Stimulation of Ca2+ currents in Y I cells is abol
ished by treatment of cells with pertussis toxin (39). This observation con
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
firms a previous finding that pertussis toxin abolishes the stimulation of 45Ca2+ influx by angiotensin II (54). In pituitary GH3 cells, pertussis toxin not only abolishes the inhibitory but also the stimulatory Ca2+ current modulation (80). Consistent with this observation is the finding that both stimulatory and inhibitory hormones stimulate high-affinity GTPases in membranes from GH3 cells (representing the enzymatic activity of G proteins ) and that this effect is sensitive to pertussis toxin (72). Thus in GH3 cells both stimulatory and inhibitory hormones apparently modulate Ca2+ channels via pertussis toxin-sensitive G proteins.
Independency of cAMP
While Ca2+
currents in cardiac and skeletal
myocytes are stimulated by cAMP-dependent phosphorylation (Trautwein & Hescheler, this volume), the stimulatory modulation of Ca2+ currents in adrenocortical and pituitary cells appears to be independent of cAMP for several reasons. (a) Intracellularly applied cAMP or extracellularly applied forskolin does not stimulate Ca2+ currents in Y l or GH3 cells (39, 80). (b) In
membranes of adrenocortical and pituitary cells, angiotensin II does not stimulate but rather inhibits adenylate cyclase (23, 80, 98). (c) LHRH does not affect adenylate cyclase activity in membranes of GH3 cells (80). (d) The sensitivity of the stimulatory Ca2+ current modulation towards pertussis toxin further indicates that elevation of cAMP is not an intermediate step since
stimulation of adenylate cyclase is mediated by G., a G protein that is a substrate for cholera toxin but not for pertussis toxin (Brown & Birnbaumer, this volume).
Possible involvement of phospholipases
In adrenocortical
(24, 54) and
pituitary cells (64, 69), angiotensin II, LHRH, and thyrotropin-releasing
hormone (TRH) stimulate a phospholipase C and, thereby, phosphoinositide hydrolysis via pertussis toxin-insensitive mechanisms. It is, therefore, un likely that activation of protein kinase C or mobilization of intracellularly stored Ca2+ via this pathway is involved in the Ca2+ current stimulation by angiotensin II and LHRH'
Another possible mechanism underlying the agonist-induced Ca2+ current
G PROTEINS AND Ca2+ CHANNELS
283
stimulation is the liberation of arachidonic acid by receptor-mediated, per tussis toxin-sensitive activation of a phospholipase A (see above). In Yl 2 cells, a protein kinase C-activating phorbol ester did not affect Ca2+ currents nor did cGMP affect the Ca2+ current stimulation by angiotensin n
(39). It
remains to be determined whether or not either of these pathways activated by arachidonic acid provides a mechanism for the stimulatory control of Ca2+ currents in pituitary cells. In both adrenocortical and pituitary cells the direct effect of arachidonic acid or its metabolites on Ca2+ channel activity has not
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
been examined. While the data reviewed above are consistent with a membrane-confined mechanism, other investigators suggest that cytosolic components are re quired for the stirilUlatory Ca2+ current modulation in pituitary cells. Taking advantage of the cell-attached variation of the patch-clamp technique, Mason
& Waring (65) found that cation channels permeable to Ca2+ are stimulated by LHRH applied to the bath solution, which therefore suggested the involve ment of a cytosolic messenger. It is however, not clear, whether the cation channels activated by LHRH represent classical voltage-dependent Ca2+ channels. Measuring cytosolic Ca2+ with a fluorescent Ca2+ chelator, Shan gold
& colleagues (86) showed that a protein kinase C-activating phorbol
ester promotes the portion of the LHRH-induced increase in cytosolic Ca2+, which apparently depends on nitrendipine-sensitive Ca2+ influx. Pertussis toxin was not applied in either of these studies.
Identity of the G protein involved in the pertussis toxin-sensitive stimulatory ccl+ channel modulation Data from reconstitution experiments with puri fied G proteins are still missing. Since only two groups of pertussis toxin sensitive G proteins are known in nonretinal tissues (i.e.
OJ and Go), and since
Go apparently mediates inhibition of Ca2+ currents, it appears plausible that a
Gj-type G protein is involved in the pertussis toxin-sensitive stimulation of voltage-dependent Ca2+ channels. This hypothesis is supported by the finding that membranes of Yl cells contain G proteins of the Gj-type, but are devoid of Go
(39). The hypothesis is also consistent with the finding that membranes
of GH3 cells possess-besides large amounts of Go-at least two Gj-type G proteins (80). CARDIAC AND SKELETAL MYOCYTES
The cholera toxin-sensitive G pro
tein, Gs. confers hormonal activation to adenylate cyclase. This leads to stimulation of cAMP-dependent protein kinase, which, in tum, activates cardiac Ca2+ channels (Trautwein
& Hescheler, this volume). Similarly.
cAMP-dependent protein kinase phosphorylates and, thereby. activates the L-type Ca2+ channel purified from T tubules of skeletal muscle (30). Recent evi in the inhibitory regulation of neuronal calcium channels. Adv. 2nd Messenger Phosphoprotein Res. 2 1 :
1 65-74
42. Higashida, H . , Streaty, R. A . , Klee, W . , Nirenberg , M. 1986. Bradykinin activated transmembrane signals are coupled via No or Ni to production of inositol 1 ,4,5-trisphosphate, a second messen ger in NGI08-1S neuroblastoma glioma hybrid cells. Proc. Natl. Acad. Sci. USA 83:942-46 43 . Holz, G. G. IV, Ranc, S. G . , Dunlap, K. 1986. GTP-binding proteins mediate transmitter inhibition of voltage dependent calcium channels. Nature 3 1 9:67�72 44. Hughes, B. P . , Crofts, J. N . , Auld, A . M . , Read, L. C. , Barritt, G. 1987. Evi dence that a pertussis toxin-sensitive substrate is involved in the stimulation by epidermal growth factor and vaso pressin of plasma-membrane Ca2+ in flow in hepatocytes. Biochem. 1. 248:91 1-18 45. Imoto, Y . , Yatani, A., Reeves, J . P., Codina, J., Bimbaumer, L . , Brown, A . M . 1 988. a-subunit o f Gs directly acti vates cardiac calcium channels in lipid bilayers. Am. J. Physiol. 255:H72228 46. Inoue, K . , Kenimer, J. 1988. Muscarin ic stimulation of calcium influx and nor epinephrine release in PC1 2 cells. J. Bioi. Chem. 263:81 57-61 47. Inoue, R . , Isenberg, G. 1989. Receptor operated currents in ileal smooth muscle cells: G�proteins involved in transduc tion for muscarinic acetylcholine recep-
tors to non-specific cation channels. J. Physiol. In press 48. Irvine, R. F . , Moor, R. M. 1987. Inosi tol ( l , 3 ,4,5) tetrakisphosphatc-induced activation of sea urchin eggs requires the presence of inositol trisphosphate. Biochem. Biophys. Res. Commun. 1 46:284-90 49. Jakobs, K. H. , Aktories, K . , Minuth, M . , Schultz, G. 1985. Inhibition of adenylate cyclase. Adv. Cycl. Nucleo tide Protein Phosphorylation Res. 1 9: 1 37-50 50. Kaczmarek, L. K. 1988. The regulation of neuronal calcium and phosphoryla tion. Adv. 2nd Messenger Phosphopro tein Res. 22: 1 1 3-38 5 1 . Kasai, H . , Aosaki, T. 1989. Modulation of Ca-channel current by an adenosine analog mediated by a GTP-binding pro tein in chick sensory neurons. Pfliigers Arch. 414: 145-49 52. Kim, D . , Lewis, D. , Graziadei, L . , Neer, E. 1 . , Bar-Sagi, D . , Clapham, D . E. 1 989. G-protein J3y-subunits activate the cardiac muscarinic K + channels via a phospholipase A2. Nature 337:557-60 53. Kimura, N . , Shimada, N. 1 988. Direct interaction between membrane-associat ed nucleoside diphosphate kinase and GTP-binding proteins (G,), and its regu lation by hormones and guanine nuc leotides. Biochem. Biophys. Res. Com mun. 1 5 1 :248-56 54. Kojima, I . , Shibata, H . , Ogata, E. 1 986. Pertussis toxin blocks angiotensin II-induced calcium influx but not inosi tol trisphosphate production in adrenal glomerulosa cell . FEBS Lett. 204:34751 55. Kuno, M . , Gardner, P . 1987. Ion chan nels activated by inositol 1 ,4 ,5trisphosphate in plasma membrane of human T-Iymphocytes. Nature 326:3014 56. Lacerda, A. E. , Rampe, D . , Brown , A . M . 1988. Effects o f protein kinase C activators on cardiac Ca2+ channels. Na ture 335 :249-5 1 57. Lefkowitz, R. 1 . , Caron, M. C. 1988. Adrenergic receptors. 1. Bioi. Chem. 263:4993-96 58. Lewis, D . L . , Weight, F. F . , Luini, A. 1986. A guanine nucleotide-binding pro tein mediates the inhibition of voltage dependent calcium current by somatosta tin in a pituitary cell line. Proc. Natl. Acad. Sci. USA 83:9035-39 59. Light, D . , Ausiello, D . , Stanton, B. 1 989. G-protein regulation of a cation channel in renal ep ithelial c"lls. J. Clin. Invest. 84:352-56 60. Lux, H . , Toselli, M . , Tokutomi, N.
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
G
PROTEINS AND Ca2+ CHANNELS
1 989. Transmitter-modulation of neuro nal Ca channels. Pfliigers Arch. 4 1 3 : R48 (Supp! .) 6 1 . MacDougall, S . L., Grinstein, S., Gel fand, E. W. 1988. Detection of ligand activated conductive Ca2+ channels in human B lymphocytes. Cell 54:229-34 62. Marchetti, c . , Brown, A. M . 1988. Pro tein kinase activator 1 -0Ieyl-2-acetyl-sn glycerol inhibits two types of calcium currents in GH3 cells. Am. J. Physiol. 254:C206-1 O 63. Marchetti, c . , Carbone, E . , Lux, H . D . 1986. Effects o f dopamine and nor adrenaline on Ca channels of cultured sensory and sympathetic neurons of chick. Pfliigers Arch. 406: 1 04-1 1 64. Martin, T. F. J . , BajjaJieh, S. M . , Lucas, D . O . , Kowalchyk, J. A . 1986. Thyrotropin-releasing hormone stimula tion of polyphosphoinositide hydrolysis in GH3 cell membranes is GTP de pendent but insensitive to cholera or per tussis toxin. J. BioI. Chem. 261 : 10 1 4 143 65. Mason, W . , Waring, D. 1986. Patch clamp recordings of single ion channel activation by gonadotropin-releasing hormone in ovine pituitary gonado trophs. Neuroendocrinology 43:20519 66. Mattera, R . , Graziano, M . P. , Yatani, A . , Zhou, Z. , et a!. 1989. Splice vari ants of the G protein Gs activate both adenylyl cyclase and calcium channels. Science 243:804--7 67. Milligan, G . , Gierschik, P. , Spiegel, A . M . , Klee, W . A . 1 986. The GTP binding regulatory proteins of neuroblas toma x glioma, NGI08- 1 5 , and glioma C6, cells. FEBS Lett. 195:225-30 68. Morris, A. P ., Gallacher, D. V . , Irvine, R. F . , Petersen , O. H. 1987. Synergism of inositol trisphosphate and tetrakis phosphate in activating Ca2+ -dependent K+ channels. Nature 330:635--55 69. Naor, Z . , Azrad, A . , Limor, R . , Zakut, H . , Lotan, M. 1986. Gonadotropin releasing hormone activates a rapid Ca2+ -independent phosphodiester hy drolysis of polyphosphoinositides in pituitary gonadotrophs. J. Bioi. Chem. 26 1 : 1 2506-1 2 70. Nelson, M . T . , Standen, N . B . , Brayden, J. E . , Worley, J. F. III. 1988. Noradrenaline contracts arteries by activating voltage-dependent calcium channels. Nature 336:382-85 7 1 . Ng, J . , Fredholm, B. B . , Jondal, M. , Andersson, T. 1988. Regulation of re ceptor-mediated calcium influx across the plasma membrane in a human leukemic T-cell line: evidence of its de-
291
pendence on an initial calcium mobiliza tion from intracellular stores. Biochim. Biophys. Acta 97 1 :207-1 4 72. Offermanns, S . , Schultz, G . , Rosenthal, W. 1 989. Secretion-stimulating and secretion-inhibiting hormones stimulate high-affinity pertussis-toxin-sensitive GTPases in membranes of a pituitary cell line. Eur. J. B iochem . 1 80:283-87 73. Okya, Y., Kitamura, K . , Kuriyama, H . 1987. Modulation o f ionic currents i n smooth muscle walls o f the rabbit in testine by intracellularly perfused ATP and cyclic AMP. Pfliigers Arch. 408: 465-73 74. Osugi, T . , Imaizumi, T . , Mizushima, A . , Uchida, S . , Yoshida, H. 1 987. Role of a protein regulating guanine nucleotide binding in phosphoinositide breakdown and calcium mobilization by bradykinin in neuroblastoma x glioma hybrid NGI08- 1 5 cells: Effects of per tussis toxin and cholera toxin on recep tor-mediated signal transduction. Eur. J. Pharmacol. 1 37:207- 1 8 75. Otero, A. S . , Breitwieser, G . E . , Szabo, G. 1988. Activation of muscarinic potassium currents by ATP-yS in atrial cells. Science 242:443--45 76. Paupardin-Tritsch, D . , Hammond, c., Gerschenfeld, H . M., Nairn, A . C . , Greengard, P. 1 986. cGMP-dependent protein kinase enhances Ca + current and potentiates the serotonin-induced Ca2+ current increase in snail neurons. Nature 323: 8 1 2-1 4 77. Penner, R . , Matthews, G . , Neher, E . 1 988. Regulation o f calcium influx by second messengers in rat mast cells. Na ture 334:499-504 78. Rane, S . G . , Dunlap, K. 1986. Kinase C activator 1 ,2-0Ieoylacetylglycerol atten uates voltage-dependent calcium current in sensory neurons. Proc. Natl. Acad. Sci. USA 8 3:1 84--88 79. Reuter, H. 1983 . Calcium channel mod ulation by neurotransmitters, enzymes and drugs. Nature 30 1 :569-74 80. Rosenthal, W . , Hescheler, J . , Hinsch, K . -D . , Spicher, K . , Trautwein, W. , Schultz, G. 1988. Cyclic AMP independent, dual regulation of voltage dependent Ca2+ currents by LHRH and somatostatin in a pituitary cell line. EMBO J. 7 : 1 627-33 8 1 . Schettini, G . , Meucci, 0 . , Florio, T . , Grimaldi, M . , Landolfi, E. , Magri, G . , Yasumoto, T. 1988. Pertussis toxin pre treatment abolishes dihydropyridine in hibition of calcium flux in the 235-1 pituitary cell line. Biochem. Biophys. Res. Commun. 1 5 1 :361-69
Annu. Rev. Physiol. 1990.52:275-292. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/04/15. For personal use only.
292
SCHULTZ ET AL
82. Schroeder, J. E . , Fischbach, P. S . , Mamo, M . , McClesky, E . W . 1989. Mu opioids inhibit calcium channels. Bio phys. J. 55:38a 83. Scott, R . H., Dolphin, A. C. 1986. Regulation of calcium currents by a GTP analogue: potentiation of (-)-bacIofen mediated inhibition. Neurosci. Lett. 69: 59-64 84. Seifert, R . , Rosenthal, W . , Schultz, G . , Wieland, T., Gierschik, P . , Jakobs, K . H. 1988. The role o f nucleoside diphosphate kinase reactions in G pro tein activation of NADPH oxidase by guanine and adenine nucleotides. Eur. J. Biochem. 175:51-55 85. Seifert, R. , Schachtele, C . , Rosenthal , W. , Schultz, G. 1988. Activation of protein kinase C by cis- and trans-fatty acids and its potentiation by di acylglycerol . Biochem. Biophys. Res. Commun. 154:20-26 86. Shangold, G . , Murphy, S . , Miller , R . 1988. Gonadotropin-releasing hormone induced Ca2+ transients in single identi fied gonadotropes require both in tracellular Ca2+ mobilization and Ca2+ influx. Proc. Natl. Acad. Sci. USA 85: 6566--70 87. Snyder, P. M . , Krause, K.-H., Welsh, M. J. 1988. Inositol trisphosphate iso mers, but not inositol 1 ,3,4,5, tetrakisphosphate , induce calcium influx in Xenopus laevis oocytes . J. Bioi. Chem. 263:1 1048-51 88. Suzuki, N . , Yoshioka, T. 1987. Differ ential blocking action of synthetic w conotoxin on components of Ca2+ chan nel current in clonal GH3 cells. Neuro sci. Lett. 75:235-39 89. Toselli, M . , Lux, H. D. 1989. GTP binding proteins mediate acetylcholine inhibition of voltage-dependent calcium channels in hippocampal neurons. Pflug ers Arch. 4 1 3: 3 1 9-21 90. Tsien, R . W., Lipscombe, D., Madison, D. V . , Bl ey , K. R . , Fox, A. P. 1988. MUltiple types of neuronal calcium channels and their selective modulation. Trends Neurosci. 1 l :431-37 9 1 . Tsunoo, A . , Yoshii, M . , Narahashi, T. 1986. Block of calcium channels by en kephalin and somatostatin in neuroblas toma-glioma hybrid NG108-15 cells. Proc. Natl. Acad. Sci. USA 83:9832-36
92. VanDongen, A. M. J. , Codina, J . , 0late, J . , Mattera, R. , Joho, R. , e t al. 1988. Newly identified brain potassium channels gated by the guanine nucleotide binding protein Go. Science 242: 143337 93. Vilven, I . , Coronado, R . 1988. Opening of dihydropyridine calcium channels in skeletal muscle membranes by inositol trisphosphate. Nature 336:587-89 94. Vivaudou, M. B . , Clapp , L. H. , Walsh, J. V. Ir., Singer, J. J. 1988. Regulation of one type of Ca2+ current in smooth muscle cells by diacylglycerol and acetylcholine. FASEB J. 2:2497-504 95. von Tschamer, V . , Prod'hom, B . , Bag gioJini, M . , Reuter, H. 1986. Ion chan nels in human neutrophils activated by a rise in free cytosolic calcium concentra tion. Nature 324:369-72 96. WallnOfer, A . , Cauvin, C. Riiegf , U. 1987. Vasopressin increases 45Ca + in flux in rat aortic smooth muscle cells. Biochem. Biophys. Res. Commun. 148: 273-78 97. Wanke, E . , Ferroni, A . , MalgaroJi, A . , Ambrosini, A . , Pozzan, T . , Meldolesi, J . 1 987. Activation of a muscarinic re ceptor selectively inhibits a rapidly in activated Ca2+ current in rat symphathe tic neurons. Proc. Natl. Acad. Sci. USA 84:43 1 3-17 98. Woodcook E., McLeod, I. 1986. Adenylate cyclase inhibition is not in volved in the adrenal steroidogenic re sponse to angiotensin II. Endocrinology 1 19: 1 697-702 99. Yatani, A . , Brown, A. M. 1989. Time course of Ca2+ current after a concentra tion jump of isoproterenol. Science 245:71-74 100. Yatani, A . , Codina, I . , Imoto, Y . , Reeves, J. P. , Birnbaumer, L. , Brown, A. M. 1 987. A G protein directly reg ulates mammalian cardiac calcium chan nels . Science 238: 1 288--92 1 0 1 . Yatani, A . , Mattera, R . , Codina, J . , Graf, R. , Okabe, K . , et al. 1988. The G protein-gated K + channel is stimulated by three distinct Gja-subunits. Nature 336:680-82 102. Z
