Biochimica et Biophysica Acta 1842 (2014) 2533–2534
Contents lists available at ScienceDirect
Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbadis
Preface
The role of soluble adenylyl cyclase in health and disease
In mammals, two distinct families of adenylyl cyclase synthesize the nearly universal second messenger cAMP. Transmembrane adenylyl cyclases (tmACs) are obligatory membrane proteins regulated by heterotrimeric G proteins; they mediate intracellular responses to extracellular signals such as hormones and neurotransmitters. In contrast, soluble adenylyl cyclase (sAC) is specifically targeted to intracellular domains and organelles, where it is positioned to provide the second messenger activating the intracellular and intra-organellar targets of cAMP. Also distinct from tmACs, sAC is regulated by intrinsic cellular signals. sAC activity is sensitive to variations in intracellular concentrations of ATP, calcium (Ca2+) and bicarbonate (HCO− 3 ) ions. Due to the ubiquitous presence of carbonic anhydrases, which catalyze the instantaneous equilibration of carbon dioxide (CO2), HCO− 3 , and protons, mammalian sAC, and its HCO− 3 -regulated orthologs throughout the bacterial and animal kingdoms, serve as Nature's physiological CO2/HCO− 3 /pHi sensors. This special issue highlights recent progress in understanding the diverse physiological roles of sAC and the relationship between CO2/HCO− 3 /pHi sensing and cAMP signaling. Cyclic AMP was discovered in the 1950's by Dr. Earl Sutherland; for this work, he was awarded the 1971 Nobel Prize for Physiology or Medicine [1]. In the decades following its discovery, research into the functions of cAMP in mammals created a conundrum; there seemed to be too many physiological processes, including opposing effects, which were revealed to be mediated by this single second messenger. In the 1980's, the work by Laurence Brunton and co-workers suggested that compartmentalization into cAMP signaling microdomains might explain how a single second messenger could mediate multiple, apparently disparate effects in a single cell [2]. This concept was not widely embraced until nearly two decades later, when Johannes Hell and co-workers demonstrated that hormonally-stimulated cAMP acted locally at the plasma membrane [3]. Since then, it has become clear that cAMP signaling is compartmentalized; cAMP is a locally acting second messenger which functions in the context of a microdomain comprised of its source (adenylyl cyclase), its targets [i.e., Protein Kinase A (PKA), cyclic nucleotide regulated channels (i.e.. cyclic nucleotide gated channels and hyperpolarization-activated, cyclic nucleotide-gated channels) and small G protein exchange proteins activated by cAMP (EPACs)], and the means of its degradation (i.e., phosphodiesterases), which prevents its spread beyond the microdomain and temporally controls the cAMP signal [4]. When we began our studies of soluble adenylyl cyclase, the only known sources of cAMP were the family of G protein-regulated transmembrane adenylyl cyclases (tmACs), which are anchored at the plasma-membrane. (Since then, tmACs have been found to also function during internalization.) Yet we knew targets of cAMP (i.e., PKA
http://dx.doi.org/10.1016/j.bbadis.2014.09.009 0925-4439/© 2014 Elsevier B.V. All rights reserved.
and EPACs) could be found inside the cell, associated with the cytoskeleton, centrioles, mitochondria, and nucleus, so we hypothesized that there might be an intracellular source of cAMP. We were aware of the work of Theodor Braun identifying a soluble adenylyl cyclase activity which seemed to be biochemically distinct from tmACs [5]. This cytosolic activity was only ever detected in testis [6], and it was presumed to be molecularly related to a bicarbonate-responsive cAMP producing activity found in mature sperm [7,8]. We sought the molecular identity of this soluble adenylyl cyclase activity to determine whether it might define a general intracellular source of cAMP. We purified a ~50 kDa protein with soluble adenylyl cyclase activity from ~ 1000 rat testis, obtained peptide sequence, and isolated cDNAs encoding the ADCY10 gene [9]. Cloning sAC allowed us to confirm that it is biochemically distinct from tmACs, and that it resides inside cells at locations coinciding with intracellular targets of cAMP [10]. Cloning sAC also yielded three initial surprising discoveries. First, sAC represents the more ancient nucleotidyl cyclase in animals. Mammalian sAC is more closely related to adenylyl cyclases from cyanobacteria, which first evolved over 3 billion years ago, than it is to the other forms of nucleotidyl cyclases (tmACs, mGCs and sGCs) found in the animal kingdom [9]. Second, sAC is widely expressed. In contrast to the initial biochemical studies suggesting it would be testis/sperm-specific, sAC is detected throughout the body [11]. Finally, sAC is directly regulated by bicarbonate anions [12,13]. Because bicarbonate is in nearly instantaneous equilibrium with CO2 and pH, bicarbonate regulation of sAC provided a previously unappreciated mechanism for sensing CO2 and pH, and numerous studies have since established that mammalian sAC, and evolutionarily-related, bicarbonate-regulated nucleotide cyclases, serve as Nature's CO2/HCO− 3 /pHi sensors [11,14]. The articles in this special issue provide more details about these surprises, and they summarize the current state of research into sAC and the evolutionarily conserved relationship between CO2/HCO− 3 /pHi sensing and cAMP. We thank all the contributors for their excellent articles and our reviewers who provided cogent, timely reviews. We also thank the Executive Editors, Drs. Jeffrey Keller and Ronald Oude Elferink, for the opportunity to serve as guest editors and Andy Deelen, Anne Ruimy, Don Prince and the production and printing staff at Elsevier for their support and help in compiling this special issue. Finally, we look forward to future studies in this rapidly expanding field and we are excited to learn what new surprising insights into biology sAC will teach us. References [1] E.W. Sutherland, Nobel prize in physiology or medicine 1971: the action of hormones outlined, Lakartidningen 68 (1971) 4991–4995. [2] J.S. Hayes, L.L. Brunton, Functional compartments in cyclic nucleotide action, J. Cyclic Nucleotide Res. 8 (1982) 1–16.
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[3] M.A. Davare, V. Avdonin, D.D. Hall, E.M. Peden, A. Burette, R.J. Weinberg, M.C. Horne, T. Hoshi, J.W. Hell, A beta2 adrenergic receptor signaling complex assembled with the Ca2+ channel Cav1.2, Science 293 (2001) 98–101. [4] K. Lefkimmiatis, M. Zaccolo, cAMP signaling in subcellular compartments, Pharmacol. Ther. 143 (2014) 295–304. [5] T. Braun, R.F. Dods, Development of a Mn-2+-sensitive, “soluble” adenylate cyclase in rat testis, Proc. Natl. Acad. Sci. U. S. A. 72 (1975) 1097–1101. [6] E.J. Neer, Physical and functional properties of adenylate cyclase from mature rat testis, J. Biol. Chem. 253 (1978) 5808–5812. [7] D.L. Garbers, D.J. Tubb, R.V. Hyne, A requirement of bicarbonate for Ca2+-induced elevations of cyclic AMP in guinea pig spermatozoa, J. Biol. Chem. 257 (1982) 8980–8984. [8] N. Okamura, Y. Tajima, A. Soejima, H. Masuda, Y. Sugita, Sodium bicarbonate in seminal plasma stimulates the motility of mammalian spermatozoa through direct activation of adenylate cyclase, J. Biol. Chem. 260 (1985) 9699–9705. [9] J. Buck, M.L. Sinclair, L. Schapal, M.J. Cann, L.R. Levin, Cytosolic adenylyl cyclase defines a unique signaling molecule in mammals, Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 79–84. [10] J.H. Zippin, Y. Chen, P. Nahirney, M. Kamenetsky, M.S. Wuttke, D.A. Fischman, L.R. Levin, J. Buck, Compartmentalization of bicarbonate-sensitive adenylyl cyclase in distinct signaling microdomains, FASEB J. 17 (2003) 82–84. [11] L.R. Levin, J. Buck, Physiological roles of acid-base sensors, Annu. Rev. Physiol. 77 (2014) (in press). [12] Y. Chen, M.J. Cann, T.N. Litvin, V. Iourgenko, M.L. Sinclair, L.R. Levin, J. Buck, Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor, Science 289 (2000) 625–628. [13] S. Kleinboelting, A. Diaz, S. Moniot, J. van den Heuvel, M. Weyand, L.R. Levin, J. Buck, C. Steegborn, Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate, Proc. Natl. Acad. Sci. U. S. A. 111 (2014) 3727–3732. [14] M. Tresguerres, J. Buck, L.R. Levin, Physiological carbon dioxide, bicarbonate, and pH sensing, Pflugers Arch. 460 (2010) 953–964.
Jochen Buck, I have been studying signaling molecules throughout my scientific career. In post-doctoral studies at Sloan Kettering Institute and as an Assistant Professor at Weill Medical College I purified and characterized an autocrine B cell factor, the kit ligand (also called stem cell factor), retinol dehydratase, and a class of signaling molecules derived from retinol, the retro-retinoids. In 1999, I collaborated with Dr. Lonny Levin to purify and clone bicarbonateregulated soluble adenylyl cyclase (sAC). We have since merged our research programs, and we are characterizing sAC, and evolutionarily related bicarbonate or pH regulated adenylyl cyclases, together.
Lonny Levin, I have been studying the cAMP signaling pathway for my entire scientific career. In graduate school, I studied the mechanism of cAMP regulation of Protein Kinase A in the yeast, Saccharomyces cerevisiae. During my post-doctoral training, I cloned and characterized the Rutabaga adenylyl cyclase, which is integral for learning and memory formation in Drosophila melanogaster. I began my career as a faculty member at Weill Cornell Medical College cloning and characterizing additional hormone-regulated adenylyl cyclases from D. melanogaster. In 1999, I collaborated with Dr. Jochen Buck to purify and clone bicarbonateregulated soluble adenylyl cyclase (sAC). We have since merged our research programs, and we are characterizing sAC, and evolutionarily related bicarbonate or pH regulated adenylyl cyclases, together.
Jochen Buck Lonny R. Levin Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA Corresponding authors: Tel.: +1 212 746 6274, +1 212 746 6752. E-mail addressess: [email protected] (J. Buck), [email protected] (L.R. Levin).
Contents lists available at ScienceDirect
Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbadis
Preface
The role of soluble adenylyl cyclase in health and disease
In mammals, two distinct families of adenylyl cyclase synthesize the nearly universal second messenger cAMP. Transmembrane adenylyl cyclases (tmACs) are obligatory membrane proteins regulated by heterotrimeric G proteins; they mediate intracellular responses to extracellular signals such as hormones and neurotransmitters. In contrast, soluble adenylyl cyclase (sAC) is specifically targeted to intracellular domains and organelles, where it is positioned to provide the second messenger activating the intracellular and intra-organellar targets of cAMP. Also distinct from tmACs, sAC is regulated by intrinsic cellular signals. sAC activity is sensitive to variations in intracellular concentrations of ATP, calcium (Ca2+) and bicarbonate (HCO− 3 ) ions. Due to the ubiquitous presence of carbonic anhydrases, which catalyze the instantaneous equilibration of carbon dioxide (CO2), HCO− 3 , and protons, mammalian sAC, and its HCO− 3 -regulated orthologs throughout the bacterial and animal kingdoms, serve as Nature's physiological CO2/HCO− 3 /pHi sensors. This special issue highlights recent progress in understanding the diverse physiological roles of sAC and the relationship between CO2/HCO− 3 /pHi sensing and cAMP signaling. Cyclic AMP was discovered in the 1950's by Dr. Earl Sutherland; for this work, he was awarded the 1971 Nobel Prize for Physiology or Medicine [1]. In the decades following its discovery, research into the functions of cAMP in mammals created a conundrum; there seemed to be too many physiological processes, including opposing effects, which were revealed to be mediated by this single second messenger. In the 1980's, the work by Laurence Brunton and co-workers suggested that compartmentalization into cAMP signaling microdomains might explain how a single second messenger could mediate multiple, apparently disparate effects in a single cell [2]. This concept was not widely embraced until nearly two decades later, when Johannes Hell and co-workers demonstrated that hormonally-stimulated cAMP acted locally at the plasma membrane [3]. Since then, it has become clear that cAMP signaling is compartmentalized; cAMP is a locally acting second messenger which functions in the context of a microdomain comprised of its source (adenylyl cyclase), its targets [i.e., Protein Kinase A (PKA), cyclic nucleotide regulated channels (i.e.. cyclic nucleotide gated channels and hyperpolarization-activated, cyclic nucleotide-gated channels) and small G protein exchange proteins activated by cAMP (EPACs)], and the means of its degradation (i.e., phosphodiesterases), which prevents its spread beyond the microdomain and temporally controls the cAMP signal [4]. When we began our studies of soluble adenylyl cyclase, the only known sources of cAMP were the family of G protein-regulated transmembrane adenylyl cyclases (tmACs), which are anchored at the plasma-membrane. (Since then, tmACs have been found to also function during internalization.) Yet we knew targets of cAMP (i.e., PKA
http://dx.doi.org/10.1016/j.bbadis.2014.09.009 0925-4439/© 2014 Elsevier B.V. All rights reserved.
and EPACs) could be found inside the cell, associated with the cytoskeleton, centrioles, mitochondria, and nucleus, so we hypothesized that there might be an intracellular source of cAMP. We were aware of the work of Theodor Braun identifying a soluble adenylyl cyclase activity which seemed to be biochemically distinct from tmACs [5]. This cytosolic activity was only ever detected in testis [6], and it was presumed to be molecularly related to a bicarbonate-responsive cAMP producing activity found in mature sperm [7,8]. We sought the molecular identity of this soluble adenylyl cyclase activity to determine whether it might define a general intracellular source of cAMP. We purified a ~50 kDa protein with soluble adenylyl cyclase activity from ~ 1000 rat testis, obtained peptide sequence, and isolated cDNAs encoding the ADCY10 gene [9]. Cloning sAC allowed us to confirm that it is biochemically distinct from tmACs, and that it resides inside cells at locations coinciding with intracellular targets of cAMP [10]. Cloning sAC also yielded three initial surprising discoveries. First, sAC represents the more ancient nucleotidyl cyclase in animals. Mammalian sAC is more closely related to adenylyl cyclases from cyanobacteria, which first evolved over 3 billion years ago, than it is to the other forms of nucleotidyl cyclases (tmACs, mGCs and sGCs) found in the animal kingdom [9]. Second, sAC is widely expressed. In contrast to the initial biochemical studies suggesting it would be testis/sperm-specific, sAC is detected throughout the body [11]. Finally, sAC is directly regulated by bicarbonate anions [12,13]. Because bicarbonate is in nearly instantaneous equilibrium with CO2 and pH, bicarbonate regulation of sAC provided a previously unappreciated mechanism for sensing CO2 and pH, and numerous studies have since established that mammalian sAC, and evolutionarily-related, bicarbonate-regulated nucleotide cyclases, serve as Nature's CO2/HCO− 3 /pHi sensors [11,14]. The articles in this special issue provide more details about these surprises, and they summarize the current state of research into sAC and the evolutionarily conserved relationship between CO2/HCO− 3 /pHi sensing and cAMP. We thank all the contributors for their excellent articles and our reviewers who provided cogent, timely reviews. We also thank the Executive Editors, Drs. Jeffrey Keller and Ronald Oude Elferink, for the opportunity to serve as guest editors and Andy Deelen, Anne Ruimy, Don Prince and the production and printing staff at Elsevier for their support and help in compiling this special issue. Finally, we look forward to future studies in this rapidly expanding field and we are excited to learn what new surprising insights into biology sAC will teach us. References [1] E.W. Sutherland, Nobel prize in physiology or medicine 1971: the action of hormones outlined, Lakartidningen 68 (1971) 4991–4995. [2] J.S. Hayes, L.L. Brunton, Functional compartments in cyclic nucleotide action, J. Cyclic Nucleotide Res. 8 (1982) 1–16.
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Preface
[3] M.A. Davare, V. Avdonin, D.D. Hall, E.M. Peden, A. Burette, R.J. Weinberg, M.C. Horne, T. Hoshi, J.W. Hell, A beta2 adrenergic receptor signaling complex assembled with the Ca2+ channel Cav1.2, Science 293 (2001) 98–101. [4] K. Lefkimmiatis, M. Zaccolo, cAMP signaling in subcellular compartments, Pharmacol. Ther. 143 (2014) 295–304. [5] T. Braun, R.F. Dods, Development of a Mn-2+-sensitive, “soluble” adenylate cyclase in rat testis, Proc. Natl. Acad. Sci. U. S. A. 72 (1975) 1097–1101. [6] E.J. Neer, Physical and functional properties of adenylate cyclase from mature rat testis, J. Biol. Chem. 253 (1978) 5808–5812. [7] D.L. Garbers, D.J. Tubb, R.V. Hyne, A requirement of bicarbonate for Ca2+-induced elevations of cyclic AMP in guinea pig spermatozoa, J. Biol. Chem. 257 (1982) 8980–8984. [8] N. Okamura, Y. Tajima, A. Soejima, H. Masuda, Y. Sugita, Sodium bicarbonate in seminal plasma stimulates the motility of mammalian spermatozoa through direct activation of adenylate cyclase, J. Biol. Chem. 260 (1985) 9699–9705. [9] J. Buck, M.L. Sinclair, L. Schapal, M.J. Cann, L.R. Levin, Cytosolic adenylyl cyclase defines a unique signaling molecule in mammals, Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 79–84. [10] J.H. Zippin, Y. Chen, P. Nahirney, M. Kamenetsky, M.S. Wuttke, D.A. Fischman, L.R. Levin, J. Buck, Compartmentalization of bicarbonate-sensitive adenylyl cyclase in distinct signaling microdomains, FASEB J. 17 (2003) 82–84. [11] L.R. Levin, J. Buck, Physiological roles of acid-base sensors, Annu. Rev. Physiol. 77 (2014) (in press). [12] Y. Chen, M.J. Cann, T.N. Litvin, V. Iourgenko, M.L. Sinclair, L.R. Levin, J. Buck, Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor, Science 289 (2000) 625–628. [13] S. Kleinboelting, A. Diaz, S. Moniot, J. van den Heuvel, M. Weyand, L.R. Levin, J. Buck, C. Steegborn, Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate, Proc. Natl. Acad. Sci. U. S. A. 111 (2014) 3727–3732. [14] M. Tresguerres, J. Buck, L.R. Levin, Physiological carbon dioxide, bicarbonate, and pH sensing, Pflugers Arch. 460 (2010) 953–964.
Jochen Buck, I have been studying signaling molecules throughout my scientific career. In post-doctoral studies at Sloan Kettering Institute and as an Assistant Professor at Weill Medical College I purified and characterized an autocrine B cell factor, the kit ligand (also called stem cell factor), retinol dehydratase, and a class of signaling molecules derived from retinol, the retro-retinoids. In 1999, I collaborated with Dr. Lonny Levin to purify and clone bicarbonateregulated soluble adenylyl cyclase (sAC). We have since merged our research programs, and we are characterizing sAC, and evolutionarily related bicarbonate or pH regulated adenylyl cyclases, together.
Lonny Levin, I have been studying the cAMP signaling pathway for my entire scientific career. In graduate school, I studied the mechanism of cAMP regulation of Protein Kinase A in the yeast, Saccharomyces cerevisiae. During my post-doctoral training, I cloned and characterized the Rutabaga adenylyl cyclase, which is integral for learning and memory formation in Drosophila melanogaster. I began my career as a faculty member at Weill Cornell Medical College cloning and characterizing additional hormone-regulated adenylyl cyclases from D. melanogaster. In 1999, I collaborated with Dr. Jochen Buck to purify and clone bicarbonateregulated soluble adenylyl cyclase (sAC). We have since merged our research programs, and we are characterizing sAC, and evolutionarily related bicarbonate or pH regulated adenylyl cyclases, together.
Jochen Buck Lonny R. Levin Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA Corresponding authors: Tel.: +1 212 746 6274, +1 212 746 6752. E-mail addressess: [email protected] (J. Buck), [email protected] (L.R. Levin).
