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Review

Store-operated Ca2+ -entry and adenylyl cyclase Dermot M.F. Cooper ∗ Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom

a r t i c l e

i n f o

Article history: Received 8 February 2015 Received in revised form 13 April 2015 Accepted 15 April 2015 Available online xxx Keywords: Calcium Adenylyl cyclase Calmodulin Orai1 Stim1 SOCE

a b s t r a c t One of the longest-standing effects of SOCE is in its selective regulation of Ca2+ -sensitive adenylyl cyclase (AC) activity in non-excitable cells. Remarkably it was this source of Ca2+ (SOCE) rather than the apparent magnitude of the Ca2+ -rise that conferred AC responsiveness. The molecular basis for this dependence is now resolved in the case of adenylyl cyclase 8 (AC8). Sensors for Ca2+ and cAMP targeted to ACs have been particularly useful in dissecting the influences upon and composition of what turn out to be signalling microdomains centred on ACs. A number of physiological processes depend on the regulation by SOCE of ACs, but the issue is under-studied. Here I will expand on these topics and point to some immediate unresolved questions. © 2015 Elsevier Ltd. All rights reserved.

1. Ca2+ -sensitive ACs are regulated by SOCE The numerous points of interaction of the Ca2+ - and cAMP signalling pathways have been reviewed extensively [1,2]. The case has also been made for the added robustness of this intertwining of the two major second messenger signalling pathways at modulating physiological processes. The critical effects of cAMP signalling, for instance via effects on phosphorylation by PKA of both VGCCs [3] and IP3 receptors [4,5], are examples of the cAMP pathway affecting Ca2+ -signalling, along with direct effects on CNG channels. Acute effects of Ca2+ on cAMP signalling are provided by direct effects of Ca2+ on AC activity [6]. The nine mammalian transmembrane adenylyl cyclases can be separated into those that are directly regulated by Ca2+ , or Ca2+ /CaM, and those that are not. However even those that are superficially insensitive to Ca2+ are potentially subject to some consequence of the triggering of the breakdown of PIP2 – either due to liberation of G␤␥ subunits from Gq-linked receptors, or activation of PKC [7] or the activation by Ca2+ of CaM Kinase II or calcineurin (see Table 1 and Fig. 1).

Abbreviations: AC, adenylyl cyclase; PKA, cAMP-dependent protein kinase; EPAC, exchange protein activated by cAMP; CNG channel, cyclic nucleotide-gated channel; PKC, protein kinase C; SOCE, store-operated Ca2+ -entry; PDE, phosphodiesterase; CaM, calmodulin; AKAP, A-kinase anchoring protein; Nt, N-terminus; PM, plasma membrane; FA, focal adhesion; ECM, extracellular matrix; IM, ionomycin. ∗ Tel.: +44 1223334063; fax: +44 1223334100. E-mail address: [email protected]

The clearest influence of the Ca2+ -signalling pathway on cAMP is the regulation of the Ca2+ -sensitive ACs by SOCE. When overexpressed heterologously, AC1 and AC8 are stimulated and AC5 and AC6 are inhibited. In endogenous systems AC8 and AC5 and AC6 are regulated by SOCE [1]. This has been demonstrated both by the normal SOCE depletion of stores triggered by hormone or neurotransmitter such as bradykinin or muscarinic receptors [8–10] or by triggering store-depletion pharmacologically using thapsigargin [11,12]. Early studies confirmed that the process responsible for these effects was SOCE by blockade with APB and blockade of the channels by appropriate concentrations of La+ , while other processes that might be triggered by Ca2+ were excluded [13]. Early demonstrations that the regulation by SOCE was more than just an in vivo manifestation of an in vitro susceptibility came from the fact that the ACs and SOCE channel that regulated their activity were functionally very close, based on a number of observations. In particular, preloading of cells with BAPTA but not EGTA precluded the regulation; the efficacy of BAPTA over EGTA was interpreted as due to the high on-rate of BAPTA for Ca2+ causing Ca2+ to be intercepted before reaching a target close to the SOCE channels [14,15]. Another indication of the functional apposition of the SOCE channels and the ACs, stemmed from the relative efficacies of Ca2+ , Sr 2+ and Ba2+ at regulating these ACs in vitro versus their ability to regulate the ACs in intact cells. Thus whereas Sr2+ was 100× less effective than Ca2+ in vitro and even though it was (as is well known) poorly carried by SOCE channels, as evidenced by global cytosolic cation elevation, nevertheless the concentrations of Sr2+ that were achieved in the vicinity of the AC were apparently high enough to register substantial effects on the expressed

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Table 1 Regulation of individual ACs by the Ca2+ -signalling pathway. The effects of Ca2+ , CaM, SOC, CaMK, CaN, PKC and G␤␥ on the nine membrane-bound ACs. Isoform

Regulation by Ca2+ /CaM

SOC

CaMK/CaN

PKC

G␤␥

AC1 AC2 AC3 AC4 AC5 AC6 AC7 AC8 AC9

Activation (CaM) No Effect Activation (CaM) – Inhibition (Direct) Inhibition (Direct) – Activation (CaM) –

Activation

–

? Activation Activation ? Activation Inhibition Activation

Inhibition Activation ? – ? ? – – –

Inhibition (CaMKII) Inhibition Inhibition Activation

ACs – effectively far higher in the vicinity of the AC than the cytosolic Ca2+ -indicator reported [16]. These data reinforced the notion that the site of cation entry was in the immediate environment of the ACs. 2. Ca2+ -sensitive ACs are ineffectually regulated by modes of cytosolic Ca2+ elevation other than SOCE Contributing to the notion of the functional apposition of ACs with SOCE channels was the insensitivity of Ca2+ -sensitive ACs to other forms of Ca2+ -rise, such as that triggered by arachidonate, diacylglycerol and release of Ca2+ from intracellular stores [8,12,11,17]. Remarkably, the large residual Ca2+ -entry triggered by high concentration of ionophore when the SOCE component caused by ionophore depletion of stores is blocked cannot regulate these enzymes [8,11]. Thus the efficacy of Ca2+ was due to its source rather than the apparent absolute amount achieved. 2.1. The ineffectiveness of ionophore Much of the selectivity of the ACs for the source of the Ca2+ which regulates their activity may be explained by the formation of intimate complexes by the ACs with the SOCE machinery (see below) and not other channel elements. However the insensitivity of ACs to ionophore-mediated Ca2+ -elevation is puzzling. ACs may occur in domains that are enriched in either Ca2+ -buffers or Ca2+ -ATPases, so that the ACs do not encounter the high cytosolic concentrations that are reported by cytosolic Ca2+ -indicators. It is also reported that

Inhibition (CaN)

–

IM does not partition into lipid membranes that contain cholesterol [18], so that Ca2+ -sensitive ACs residing in cholesterol-rich lipid rafts might be shielded from IM-induced elevations in Ca2+ . Another possibility is that the Ca2+ -rise achieved by ionophore is intrinsically different from that achieved by a channel. Ionophores promote the transport of ions across membranes in a continuous, concentration-driven manner, while channels elicit rapid transitions in very high (>100 ␮M) ion concentration in the vicinity of channel mouths [19]. It is conceivable that the ACs respond to these fast digital increments rather than to the absolute amounts of Ca2+ achieved. A recent analysis of the control of sperm turning by Ca2+ entry via CNG channels raises some interesting and insightful parallels [20]. Sea urchin sperm swim towards the source of a gradient of the hormone, resact, in a dish in a manner that absolutely depends on the ability of the hormone to elevate [Ca2+ ]i. However there is not a good correlation between the [Ca2+ ]i that is achieved and the turning of the sperm; instead by modelling the rate of change – rather than the absolute amount of Ca2+ – a clear relationship emerges; the sperm turning is convincingly correlated with the time derivative of [Ca2+ ]i [20]. Although no molecular mechanisms were addressed in that study, a ‘chemical differentiation’ step was suggested. Molecular explanations that were considered included the different time constants and cooperative binding of Ca2+ to the EF hands of calmodulin. This situation could readily apply to the Ca2+ regulation of AC1 and AC8, which is mediated by CaM. Stop-flow analysis of the effects of the relevant CaM-binding domain peptides from AC8 and AC1, respectively, show quite different effects on Ca2+ binding kinetics by the N- and C-lobes of CaM [21] which could underlie a ‘chemical differentiation’ step [19] that

Fig. 1. Modes of regulation of ACs as a consequence of the activation of the PIP2 breakdown pathway in non-excitable cells. These potential regulatory interactions are based on in vitro demonstrations of the susceptibility of the ACs. The in vivo evidence for parts of this scheme has been difficult to establish in all cases [1,96]. From Ref. [1].

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could allow ACs to respond to rapid Ca2+ -gradients. The N-lobe of the CaM has extremely high affinity for Ca2+ when bound to the Nt of AC8 but this is reduced by two orders of magnitude when the CaM interacts with the C-terminus of AC8 [21]. Thus both a discrimination for very high Ca2+ concentrations is possible – as occur near the mouths of ion channels – but not at ionophores – as well as a temporal differentiation step due to the transition of the CaM from the Nt to the C-terminus resulting in a reduced affinity for Ca2+ , which delays the process (see also Ref. [19]). A chemical differentiation step is less easy to envisage for the Ca2+ -inhibitable AC5 and AC6, where inhibition by Ca2+ occurs directly by binding to the catalytic site [22,23].

3. AC8 and the long-form of Orai1 form a complex When the long search for the identity of the channel component of the SOCE apparatus led to Orai1 [24–26], the door was opened to asking directly whether the intimacy of the AC/SOCE interaction was due to a direct binding between the two proteins. Since it was known that the full length AC8 was regulated by the endogenous SOCE apparatus in HEK293 cells, but that a version of AC8 with a truncated Nt could not be regulated [27], it was reasoned that the Nt of AC8 was a strong candidate to mediate any such interaction. Initial experiments showed that the GST-tagged Nt of AC8 could indeed pull down the endogenous Orai1 of HEK 293 cells. An extension of this experiment expressed HA-tagged full-length AC8 or HA-tagged AC8 lacking the Nt and looked for coimmunoprecipitation using anti-HA antibodies from whole cells. This experiment confirmed the interaction between Orai1 and the full-length AC8, but not by the truncated version of the protein. The regions of the Orai1 responsible for the interaction with Nt of AC8 was explored by peptide array analysis of progressively overlapping 20 amino acid sequences from Orai1. A region within the first 40 residues of the Orai1 Nt appeared largely responsible for the binding. Mutating the likely arginine residues in a subsequent peptide array confirmed this significant domain [28]. A converse in vitro version of this experiment was conducted by using an MBP-tagged version of the Orai1 Nt in a pull-down assay with the GST-tagged Nt of AC8. A pull-down was observed which was precluded by mutating the five key arginine residues at the Nt of the Orai1 peptide [28]. This promising biochemical evidence led to FRET analysis of native or truncated forms of Orai1 and AC8, respectively tagged with CFP and YFP to assess the interaction in live cells. A strong FRET signal was observed, which depended on the presence of the previously highlighted AC8 N-terminal section. Again, conversely, analysis of FRET between the full length and N-terminally truncated Orai1 strongly supported this interaction as occurring between the N-terminal of both proteins. Curiously, although, as expected, a strong FRET signal was detected between Stim1 and Orai1 that depended on store depletion, the interaction between Orai1 and AC8 was stable and did not require stores to be depleted [28]. Thus the AC and its regulator appear to form a stable complex. It is worth noting that there is a short form of Orai1 (Orai1b) with an alternative translation start site which lacks the first 60 residues of Orai1a [29]. This form does not yield a FRET signal with AC8 in our experiments and thus would not be capable of interacting with – or regulating AC8. Thus the relative abundance of these forms will determine which might be in complex with AC8 and which are free. We have recently found that TrpC1 can also contribute to the SOCE complexes that regulate AC8 in HEK293 cells. Direct binding was not addressed in that study although AC8 and TrpC1 and Stim1 did co-localize by TIRF analysis [30].

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4. Orai1 and AC8 interact in lipid rafts The development of super-resolution microscopic and other live cell methods for studying lipid elements and protein within the plasma membrane (PM) [31] contribute to a picture of the PM as a heterogeneous and dynamic structure both at the protein and lipid level. Lipid rafts are the clearest manifestation of this heterogeneity, viewed to be domains that are rich in cholesterol, sphingolipids and unsaturated side chain phospholipids. The concept of lipid rafts has evolved beyond static signalling arrays to often transient ‘nanodomains’ that can accommodate multiple protein molecules [32–35], which act as devices to concentrate and promote interactions between effectors and targets [36]. Some ACs (1/3/5/6/8) are consistently associated with rafts and others (2/4/7/9) are not [37–39]. A range of evidence, including live cell methods supports this assignation [39–41]. By traditional biochemical raft fractionation both AC8, Orai1 and TrpC1 occur in lipid rafts [27,42,43] as do CNG channels [44] and L-type channels [45]. Two live cell methods showed that the interaction between full-length, but not truncated AC8 and Orai1 occurred in raft-like regions; light-guided (LG)-TIRF FRET between the two proteins was seen in a GM1-rich domain of the PM as measured by their coincidence in an alexafluor-tagged cholera toxin B subunit region of the PM (Cholera toxin B binds to GM1 gangliosides – characteristic markers of lipid rafts); fluorescence recovery after photobleaching (FRAP) also showed an interaction between the Nt of AC8 and a fluorescent ergosterol derivative, which suggested either than the AC8 Nt directly bound the cholesterol surrogate, or that the association of the AC8 with rafts promoted the interaction (Fig. 2). Disruption of the lipid rafts by extraction of cholesterol with methyl-␤-cyclodextrin destroys these interactions as well as disrupting the regulation of all ACs by SOCE [27,46], so that it might be concluded that the presence of these complexes in rafts is an essential aspect in their assembly [28]. How these proteins are targeted to rafts is unclear at present; it may be that a summation of low affinity interactions can add up to a stable presence in rafts. Thus, whereas the cytosolic regions of AC5 and AC6 seem responsible for their residence in rafts [47,48] which suggests that protein-protein interactions might underlie these associations, it may also be that other weaker (protein/lipid) interactions predispose the protein-protein interactions to occur, so that it can become difficult – or moot – to establish which property is the more robustly raft-associating.

5. ACs generate their own microenvironments Apart from binding SOCE elements, Ca2+ -sensitive ACs also directly bind other regulatory factors, most significantly AKAPs. AKAPs are critical devices in cAMP signalling that minimally bind PKA; they possess a cellular targeting domain and often an effector binding domain for the target of cAMP [49,50]. AKAPs can also bind regulatory proteins such as phosphodiesterases, protein kinase C and calcineurin. All Ca2+ -sensitive ACs bind AKAPs [51–53]; well-established examples of AC/AKAP complexes include AC5/6/AKAP79/L-type channel/PDE4D3 [54], AC8/AKAP79/PDE4D3 [55] and AC5/mAKAP in cardiomyocytes [56] (Fig. 3). It is to be expected that other targets of PKA phosphorylation, such as IP3 receptors, will utilize an AKAP in situations where the action of cAMP is local or acute rather than global. By sharing an AKAP, ACs can also act as a bridge to recruit targets of PKA such as L-type channels [57] and K+ -channels [53] to yield efficient AC-centred complexes. It is tempting to speculate on whether the binding by AC8 of AKAP79 which binds both PKA and PKC [55,58] might allow the reported phosphorylation and inactivation of Orai1 by PKC [59]. Apart from immediate regulatory factors, AC microenvironments can be sustained or created as a consequence of interactions

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Fig. 2. Binding of AC8 and Orai1 in a cholesterol-rich domain. AC8 enriches in cholesterol (purple oblongs) rich domains where it binds to Orai1 via their respective N-termini [28]. The interaction can withstand Ca2+ depletion but is disrupted by disturbing the integrity of lipid rafts or the cytoskeleton [27,28,41] (For interpretation of the references to color in figure legend, the reader is referred to the web version of the article). From Ref. [87].

with the cytoskeleton and the stabilization of lipid rafts. In fact some of the regulatory factors with which the ACs interact e.g. AKAP79, can be palmitoylated and thus have an added affinity for, and stabilizing effects on, rafts [60]. Palmitoylation of AKAP79 is required for its association with lipid rafts, which slows its diffusion from normal to anomalous sub-diffusive [60]. This property is a characteristic of less than free dissociation in the plasma membrane, and can be due to encountering obstacles such as

‘picket-fence’ effects of the actin cytoskeleton or association with other proteins whose diffusion is constrained [61–63]. In this regard a recent analysis of the dynamics of the interaction of Stim1 and Orai1 in the PM observed anomalous sub-diffusion, which was interpreted as being due to interaction with elements of rafts, that included PIP2, which is enriched at ER/PM junctions, caveolin and CRACR2A, as well as AC8 [64]. Stim1, a key component in the SOCE regulation of ACs, is a microtubule-associating protein [65]. Given

Fig. 3. AC/AKAPs complexes. Examples of different AC/AKAP complexes and their associated regulatory proteins and effectors. From Ref. [51] with permission.

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the range of interactions between ACs and variously organized proteins, a dynamic picture should be envisaged for ACs which may be transient, or stable and long-lived, involving a varying range of interactions with regulatory proteins, structural proteins and specific lipid elements of the PM.

6. Measuring Ca2+ and cAMP in AC microenvironments The developing evidence that functional domains for cAMP can be centred on ACs, coupled with the fact that every cell explored expresses multiple AC species, along with the local effects of cAMP on many processes, argues for an exploration of cAMP at this level of complexity. Cellular microdomains of cAMP have been encountered using all of the current cAMP sensors such as PKA, EPAC and CNG channels [66–68]. However, a case can be made for expecting that the cAMP dynamics around specific ACs may differ, if the local environments can maintain their independent dynamics in the light of whatever diffusive or degradative influences pervade in their domains. A step was made towards addressing this issue in pituitary-derived GH3 cells when the CFP/YFP tagged EPAC cAMPsensor was either localized to the cytosol, the PM or attached to AC8. These cells endogenously express both the Ca2+ -stimulable AC8 as well as the Ca2+ -inhibitable AC6. Contrasting changes in cAMP were reported by the different sensors in response to Gq-linked versus Gs-linked GPCRs, which supported the notion that distinct cAMP microdomains surrounded the AC8 (Ca2+ /Gq stimulable) and AC6 (Gs stimulable and Ca2+ -inhibitable) [69]. These results make a case for exploring AC-domains more widely using specific AC-tagged sensors. In this regard it seemed potentially insightful to explore the Ca2+ -dynamics in the environment of the Ca2+ -sensitive (raft-localized) AC8 compared with the Ca2+ -insensitive (raft-excluded) AC2 under the influence of SOCE or Ca2+ release from stores, by tagging the respective ACs with the fluorescent Ca2+ -reporter, GCaMPs [70]. Clear differences were observed; AC2-tagged sensors were faithful reporters of global cytosolic Ca2+ -perturbations as induced by release from stores when compared with cytosolic sensors; on the other hand they were poor at detecting the entry of Ca2+ -emanating from SOCE. Conversely AC8 hardly detected any fluctuation in Ca2+ in response to any stimulus other than that triggered by SOCE (Fig. 4) [71]. This observation underlines the different Ca2+ -dynamics in AC environments, their obviously different composition and it also powerfully supports the observation of the functional responsiveness of AC8 to SOCE and insensitivity to any other Ca2+ -rise. AC-based Ca2+ -sensors seem a useful means to explore the elevation in Ca2+ achieved by IM in AC domains, given the ineffectiveness of Ca2+ -entry mediated by IM. When Ca2+ was measured in the vicinity of an AC with a attached fluorescent protein sensor for Ca2+ , GCaMPs [70,71] a very small IM component, as well as a SOCE component, was detectable in response to IM [28,71] although this did not compare to the Ca2+ -rise reported by a cytosolic sensor [71]. Thus the lack of efficacy of IM-induced Ca2+ -entry at regulating ACs may simply be due to insufficient Ca2+ reaching the vicinity of the AC as a result of unclear mechanisms (as discussed above) and impressions conveyed by cytosolic sensors do not represent the Ca2+ concentrations in the AC domain. Another recent example of the application of these sensors was in supporting the participation of TrpC1 in some Orai1 complexes that regulate AC8 in HEK293 cells [30]. AC-tagged sensors promise to be discerning tools for assessing the influences of proteins or various manipulations in AC-domains. For instance, peptide or small molecule disruptors of scaffolding interactions, or AC/channel interactions, or siRNAs against components, could all be usefully assessed using targeted vs global sensors of the second messengers.

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7. Pharmacological implications and challenges arising from AC microdomains The principles put forward by Robison et al. [72] many years ago for implicating cAMP in hormone-stimulated processes proved extremely discerning in the early years of establishing the ubiquity and involvement of cAMP in the hormone-mediation of numerous physiological processes such as lipolysis, steroidogenesis, glycogenolysis, etc. The principles were that (i) the hormone should stimulate AC in broken cell preparations; (ii) the hormone should increase cAMP levels in intact cells at reasonable doses; (iii) the hormone effect should be potentiated by adding PDE inhibitor and (iv) the effect should be mimicked by adding exogenous cAMP [72]. Current awareness of cAMP dynamics and particularly the regulation of ACs by SOCE challenge most of these early principles. For example; (i) It is to be expected that a Gq-linked hormone could stimulate a Ca2+ -stimulated AC in the intact cell by, but the effect (of hormone) would not be seen in a broken cell preparation; (ii) Measurable, local changes in cAMP may only be detectable with very sensitive cAMP probes, so that global changes may be absent except when PDEs are inhibited, a strategy which can complicate outcomes; (iii) Inhibition of PDE certainly will change the spatial and temporal pattern of a cAMP rise, so that a mimicking of the original physiological response could be problematic, for instance in situations where oscillations in cAMP mediate effects [73]; (iv) Exogenous cAMP may only mimic effects at enormous intracellular concentrations in order to access the domain where the effect is being manifest [74] and the number of alternative pathways and cellular consequences triggered by cAMP may obscure or distort the contribution of local cAMP. Perhaps it is safer to say that these four principles may be considered in situations where cAMP compartmentalization and regulation by SOCE is not important – conceivably where the target is largely cytosolic e.g. glycogen or triglyceride breakdown. But in the absence of knowing whether or not compartmentalization or SOCE is involved a much more tentative exploratory approach seems warranted. A clear implication of the existence of distinct AC domains is the challenge and ambiguity posed by global elevation or inhibition of ACs by whatever mechanisms. Global elevation of cAMP by e.g. forskolin will (via all ACs present) trigger many of the downstream effects of cAMP, although whether cAMP will rise in the microenvironment of specific ACs stimulated by a GPCR and mimic their effects is uncertain. Inhibition of AC is similarly problematic. There is a lack of specific AC isoform inhibitors that are effective in a mixed AC cellular context [75]. Ignorance of the relative permeation properties to specific AC microdomains of the available inhibitors is a problem which might be addressed by using specific AC-tagged sensors. Although specific inhibitors of PDE isoforms exist the most difficult aspect of PDE inhibition is that the spatial and temporal qualities of cAMP signals are destroyed [76]. Whereas pulsatile cAMP might mediate a signal, a gross wave of cAMP may not mimic the effect – as clearly demonstrated by Gaspar in exuberant axon path-finding [73]. Specific AKAP disruptors are a promising new approach when disrupting the binding of a specific AKAP to a specific AC might be the goal [77,78]. AC knockdowns can be a powerful approach to identify the role of specific ACs. However the fact that ACs act as scaffolds, with the result that the knockdown of a scaffold presumably displaces attendant AKAPs and other factors, may have additional unintended consequences. In this regard it is remarkable that transgenic mice lacking the Ca2+ -regulated AC1 and AC8 can survive [79]. Nevertheless they do, which suggests a degree of plasticity in signalling, so that a Ca2+ /cAMP interplay mediated by a Ca2+ /AC1/AC8 interaction can potentially be replaced by a Ca2+ /PKC/AC2 system. Such

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Fig. 4. Distinct Ca2+ -microenvironments surround a Ca2+ -insensitive AC2 and a SOCE-stimulable AC8. Based on experiments with GCamps-tagged AC constructs selective co-localization of AC2 and AC8 with specific sites of Ca2+ entry and release. mACh, muscarinic acetylcholine; SOCE, store-operated Ca2+ entry; PLC, phospholipase C; IP3, inositol-(1,4,5)-trisphosphate. From Ref. [71].

plasticity implies it is not by the chronic deletion of a protein and the attendant adjustments that its role is uncovered but by more targeted dissections of its various functions. AC knock-ins with targeted mutations may provide more insight. The foregoing reservations should not simply question the value of some current approaches; awareness of these uncertainties speaks to our progress in understanding the elaborate and tightlyorganized roles of ACs.

historically different technologies for the study of Ca2+ and cAMP – the former were live cell and clearly required complex interactions between channels and pumps in living cells, while the cAMP system appeared more enzyme-based with downstream cascades that were amenable to dissection in broken cells in terms of enzymes, G-proteins, kinases, AKAPs, etc. and it was only with the development of single live cell methods for studying the messenger that the interaction could begin to be addressed.

8. Physiological roles for the regulation of ACs by SOCE and Ca2+

9. Future directions and outstanding questions

There have been a number of demonstrations of the physiological exploitation of the regulation of ACs by SOCE. For instance, the regulation of endothelial gap formation by thrombin critically depends on the inhibition by SOCE of cAMP produced by AC6, which otherwise opposes gap formation [80]. Aldosterone synthesis and secretion depends on the coincident stimulation by angiotensin of Ca2+ -elevation and cAMP resulting from the stimulation of a SOCEsensitive AC [81]. Elsewhere we have speculated on the likely involvement of Ca2+ -inhibitable ACs in the process of focal adhesion assembly and disassembly [82] where both Ca2+ and cAMP play major roles in FA dynamics [83,84]. The elements of SOCE, along with AKAP220, occur at focal adhesions [85,86]. Two recent reviews [87,88] summarize the consequences of AC knockout and over-expression studies which implicate ACs, many of them susceptible to regulation by SOCE, in a wide range of physiological processes. The involvement of SOCE regulation of ACs in numerous physiological processes seems highly likely, given the ubiquitous expression of SOCE and the widespread expression of Ca2+ sensitive ACs. Thoughtful reviews were presented on the essential interaction between Ca2+ and cAMP almost forty years ago [89,90]. However it is more difficult to prove the need for this interaction than simply the need for Ca2+ -entry and SOCE alone. The two systems may have been separated conceptually because of the

One of the first questions to be asked about the interaction of SOCE with ACs is whether all of the Ca2+ -sensitive (and SOCEregulated) ACs bind Orai1 directly. Although the mechanism of inhibition by low concentrations of Ca2+ of AC5 (and presumably of the very similar AC6) has been established in detail in vitro [22], down to the level of crystallographic data [23] the features required for this regulation in vivo are quite unaddressed. AC5 and AC6 may be capable of binding Orai1, as they possess long N-termini. AC1 on the other hand has only 60 N-terminal residues and in fact it does not seem as independent of release as are the other ACs [10]. The mechanism of activation of AC1 also does not involve the apparent movement of CaM between the N and C-termini [11], which eliminates one possible temporal differentiator step, so that novel mechanisms may yet emerge. Although this review has focussed on the regulation of the ACs by SOCE in non-excitable cells, these enzymes are also regulated by VGCCs, although this topic has received far less attention. Ca2+ sensitive ACs are regulated by L-type Ca2+ channels in excitable cells – both when exogenously and endogenously expressed. For instance AC8 when expressed in GH3 and pancreatic MIN6 cells is stimulated [91,92]; the AC5/6 of cardiomyocytes is inhibited and the endogenous AC1/AC8 is stimulated in hippocampal slices [93,94]. The issue of the selectivity of ACs in excitable cells for voltage-gated Ca2+ channels (VGCC) over other forms of Ca2+ entry has been considered in MIN6 cells, where stimulation of the

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endogenous AC1 was elicited by L-type Ca2+ -channels but not by SOCE or receptor-induced release from stores [95]. However in GH3 cells the equivalent comparison showed that L-type Ca2+ -channels and SOCE yielded equivalent stimulation of AC8 [91]. The availability of a less pH-sensitive cAMP sensor [92] should assist in addressing the regulation of Ca2+ -sensitive ACs in excitable cells. It seems reasonable to expect that not only will dependences on Ca2+ -entry over release be revealed but also interactions with subunits of L-type channels or at least that AC-bound AKAPs would provide a bridge to the channels as discussed above. Beyond the relatively simple question of how the ACs may be regulated by SOCE (and VGCC) is of course the nature of the AC supramolecular assemblies and how their assembly is regulated. From many experimental vantages AC assembly, organization and regulation can be complex, dynamic and depend on explicit cellular contexts. Models of solitary AC molecules awaiting interactions with G-protein subunits are no longer sustainable. Although technically challenging, engagement with this level of complexity is essential to understand signalling by cAMP and, by extension, general signalling control of cellular activity. ACs tagged with sensors for cAMP (and Ca2+ ) is one approach to unravelling AC micro-environments. Targeted sensors may also prove useful in confronting the pharmacological problems of off-target effects and others raised above. For the present, understanding the SOCE regulation of ACs has provided valuable insights into the strategies used to exploit and control the centrally important physiological regulator, cAMP.

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