Cross-talk between cAMP and Ca2+ signalling pathways plays a critical role in cellular homoeostasis. Several AC (adenylate cyclase) isoforms, catalysing the production of cAMP from ATP, display sensitivity to submicromolar changes in intracellular Ca2+ and, as a consequence, are key sites for Ca2+ and cAMP interplay. Interestingly, these Ca2+-regulated ACs are not equally responsive to equivalent Ca2+ rises within the cell, but display a remarkable selectivity for regulation by SOCE (store-operated Ca2+ entry). Over the years, considerable efforts at investigating this phenomenon have provided indirect evidence of an intimate association between Ca2+-sensitive AC isoforms and sites of SOCE. Now, recent identification of the molecular components of SOCE [namely STIM1 (stromal interaction molecule 1) and Orai1], coupled with significant advances in the generation of high-resolution targeted biosensors for Ca2+ and cAMP, have provided the first detailed insight into the organization of the cellular microdomains associated with Ca2+-regulated ACs. In the present review, I summarize the findings that have helped to provide our most definitive understanding of the selective regulation of cAMP signalling by SOCE.

Role of the ACs (adenylate cyclases) in Ca2+ and cAMP interplay

Dynamic interactions between Ca2+ and cAMP signalling underlie the control of major cellular events, including hormone and neurotransmitter release, cardiac contraction, cell migration and synaptic development [15]. Modest changes in intracellular Ca2+ can potently regulate the production and hydrolysis of cAMP via effects on Ca2+-sensitive ACs and PDEs (phosphodiesterases) respectively [6,7]. Furthermore, there is potential for bidirectional interplay, with cAMP and its effector proteins directly regulating Ca2+ entry, release and clearance pathways within the cell [8,9]. The present review focuses on new insights into the organization of discrete cellular microdomains in which the Ca2+-sensitive ACs reside and are regulated.

Of the nine membrane-bound isoforms of AC (simply referred to as AC1–AC9), four display sensitivity to submicromolar Ca2+ changes. AC1 and AC8, primarily expressed in neuronal and pancreatic tissue, are stimulated by Ca2+/CaM (calmodulin) [10,11], whereas AC5 and AC6, highly expressed in cardiac tissue and striatal neurons, are inhibited directly by Ca2+ [12,13]. Despite obvious differences in the mode of Ca2+ action at Ca2+-stimulated compared with Ca2+-inhibited ACs, these ACs share a commonality in that they are all targeted to cholesterol- and sphingolipid-enriched regions of the plasma membrane, termed lipid rafts. In contrast, Ca2+-insensitive ACs (such as AC2 and AC7) are enriched in non-raft regions of the plasma membrane, where they are preferentially regulated by other signalling molecules such as PKC (protein kinase C) [7]. In vitro, AC1, AC8, AC5 and AC6 display clear stimulation or inhibition in response to submicromolar changes in Ca2+ concentration. However, their regulation in the intact cell is more complex, exhibiting discrimination for the source of Ca2+ rise and a dependence upon local signalling proteins.

Selectivity of the ACs for SOCE (store-operated Ca2+ entry)

Earlier studies demonstrated a robust selectivity of the Ca2+-sensitive ACs for distinct routes of Ca2+ increase. In particular, the ACs were found to be highly sensitive to changes in Ca2+ arising from SOCE [1416]. In these early experiments, SOCE was typically evoked by supramaximal concentrations of Gq-coupled receptor agonist to actively deplete ER (endoplasmic reticulum) Ca2+ stores, or by passive store depletion, using SERCA (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase) pump inhibitors such as thapsigargin [1416]. Since then, stimulation of dynamic Ca2+ transients evoked by submaximal activation of Ins(1,4,5)P3-coupled receptors (giving rise to both ER store depletion and subsequent SOCE) has been shown to mediate synchronous oscillations in Ca2+ and cAMP in HEK (human embryonic kidney)-293 cells [17]. These SOCE-dependent cAMP transients were driven by the combined activities of Ca2+-stimulated AC8 and a PKA (protein kinase A)-dependent PDE (PDE4) [17].

In non-excitable cells, all Ca2+-sensitive AC isoforms are reported to exhibit high sensitivity for SOCE [1416], although a limited sensitivity to Ins(1,4,5)P3-mediated Ca2+ release has been observed in subpopulations of cells [17]. Ca2+ entry mediated via ionophore-, arachidonic acid- or OAG (1-oleoyl-2-acetylglycerol)-dependent pathways is reported to be completely ineffective with respect to AC regulation [15,18,19]. Surprisingly, studies in excitable cells have also reported a selectivity of Ca2+-sensitive ACs for regulation by SOCE, with relatively modest SOCE signals influencing AC activity to a similar degree as that mediated by larger Ca2+ signals arising from VGCCs (voltage-gated Ca2+ channels) [20]. Nevertheless, depolarization-evoked changes in Ca2+ have been shown to significantly regulate cAMP production in excitable cells [21,22]. In pancreatic cells, both phasic and antiphasic oscillations in Ca2+ and cAMP have been reported as a consequence of L-type Ca2+ channel activity, with the varied timing between Ca2+ and cAMP changes presumably due to differences in the relative expression and activation of Ca2+-sensitive ACs (AC6 and AC8) and the Ca2+/CaM-activated PDE1 [23,24]. The physiological consequences of SOCE on cAMP signalling in excitable cells remain to be determined. Although SOCE provides a fairly modest source of Ca2+ entry in excitable cells compared with the activation of VGCCs, there is a growing appreciation of the potential importance of this mode of Ca2+ entry in numerous pathological conditions [25].

Compartmentalization: indirect evidence for AC and SOCC intimacy

It has been proposed that the selectivity of AC regulation for SOCE is due to an intimate association between the Ca2+regulated ACs and SOCCs (store-operated Ca2+ channels) in discrete compartments (or ‘microdomains’) of the cell. Indirect evidence for this was first described in studies using the Ca2+-sensing photoprotein, aequorin, tagged to the C-terminus of Ca2+-inhibitable AC6. When expressed in HEK-293 cells, the AC6–aequorin chimaera reported larger Ca2+ changes during SOCE than during ER Ca2+ mobilization, despite the latter stimulus giving rise to larger cytosolic Ca2+ signals [26]. However, this study required the use of cell populations and was limited by poor spatial resolution and difficulties calibrating the Ca2+ sensor. At around the same time, assays of AC6 activity in a glioma cell line gave further support to the hypothesis that this AC was localized close to sites of SOCE, by revealing differences in the abilities of ‘fast’ {BAPTA [1,2-bis-(o-aminophenoxy)ethane-N,N,N′,N′-tetra-acetic acid]} and ‘slow’ (EGTA) Ca2+ chelators to abolish the effects of SOCE on cAMP production [16]. Loading of BAPTA attenuated the SOCE-mediated inhibition of AC6, whereas EGTA, unable to chelate rapid Ca2+ events within the immediate vicinity of AC6, was without effect. Other indirect evidence that Ca2+-regulated ACs and SOCCs may reside in close proximity to one another was provided by functional studies using enhanced AC8 activity to report increases in SOCE following co-expression of the two key molecular components of SOCE, STIM1 (stromal interaction molecule 1) and Orai1 [27]. The likely association of Ca2+-sensitive ACs with SOCCs is also supported by evidence of targeting of these ACs, alongside STIM1 and Orai1, to lipid raft regions of the cell membrane [2731].

The apparent compartmentalization of Ca2+-sensitive ACs with sites of SOCE in discrete regions of the plasma membrane is central to the dynamics of Ca2+ and cAMP interplay, enabling the ACs to respond very rapidly to modest changes in local Ca2+ levels. This has been illustrated recently following the development of GECIs (genetically encoded Ca2+ indicators) and cAMP biosensors targeted to specific AC isoforms (see later section on ‘Monitoring signalling microdomains with targeted sensors’). It is now becoming evident that the formation of stable signalling complexes within such microdomains is determined by the ability of the Ca2+-sensitive ACs to directly bind to a number of key signalling proteins [3237].

Evidence of direct protein–protein interactions in the AC microdomain

Key to the varied physiological actions of the ACs is their ability to form direct protein–protein associations with other signalling molecules, generating macromolecular signalling complexes that are capable of targeting the diverse downstream actions of cAMP and its effector molecules to specific sites within the cell [32,3437]. Such interactions can also influence the controlled production and hydrolysis of cAMP in discrete microdomains [32,3739]. Recent findings have revealed that several AC isoforms directly associate with AKAPs (A-kinase-anchoring proteins), a diverse family of scaffold proteins that primarily function to target the actions of PKA (as well as an array of other signalling molecules including phosphatases, kinases and PDEs) to select regions of the cell [40,41]. The consequences of such interactions are not yet fully understood, but AC–AKAP–PKA complexes have been shown to promote the feedback action of PKA to down-regulate AC5/AC6 activity [32,34,35] or to attenuate Ca2+-dependent stimulation of AC8 [37]. AC–AKAP associations may also target the actions of cAMP to specific ion channels to promote rapid and specific signalling from Gs-coupled receptors [42]. In addition to binding to AKAPs, specific interactions between Ca2+-regulated ACs and other proteins, including PP2A (protein phosphatase 2A) and proteins associated with synaptic function, have been reported [33,43,44].

Thus the stage has been set for ACs forming direct interactions with other proteins that optimize the efficiency of cAMP production or signalling in subcellular compartments. By combining imaging and biochemical approaches, we now have evidence of a direct protein–protein interaction between AC8 and the pore component of SOCCs, Orai1 (D. Willoughby, M.L. Halls, K.L. Everett, J. Pacheco, P. Skroblin, L. Vaca, E. Klussmann and D.M.F. Cooper, unpublished work). Data from FRET (fluorescence resonance energy transfer) studies, GST (glutathione transferase) pull-downs, co-immunoprecipitations and peptide array analyses has provided the first conclusive evidence of a direct interaction between a Ca2+-regulated AC and the source of the Ca2+ rise that regulates activity of the enzyme with such high selectivity. These latest findings go a long way towards explaining the observed functional dependence of AC regulation on SOCE. Such intimacy between AC8 and Orai1 serves to ensure the production of dynamic co-ordinated changes in levels of Ca2+ and cAMP in cells (Figure 1). It remains to be seen whether other Ca2+-sensitive AC isoforms can also form similar direct interactions with the molecular components of the SOCE pathway, thus underpinning their selectivity for this mode of Ca2+ rise.

A direct interaction between AC8 and Orai1 promotes selective regulation of cAMP production by SOCE

Figure 1
A direct interaction between AC8 and Orai1 promotes selective regulation of cAMP production by SOCE

Evidence points to AC8 residing in discrete microdomains of the cell that are exposed to large rapid Ca2+ transients as a consequence of SOCC activity, but limited Ca2+ changes arising from other sources. The direct binding of AC8 and Orai1 is central to this phenomenon. STIM1 is required for the activation of Orai1 following ER Ca2+ store depletion. The SERCA pump is required to replenish the stores by transporting Ca2+ from the cytoplasm to the ER.

Figure 1
A direct interaction between AC8 and Orai1 promotes selective regulation of cAMP production by SOCE

Evidence points to AC8 residing in discrete microdomains of the cell that are exposed to large rapid Ca2+ transients as a consequence of SOCC activity, but limited Ca2+ changes arising from other sources. The direct binding of AC8 and Orai1 is central to this phenomenon. STIM1 is required for the activation of Orai1 following ER Ca2+ store depletion. The SERCA pump is required to replenish the stores by transporting Ca2+ from the cytoplasm to the ER.

Monitoring signalling microdomains with targeted sensors

Recent years have witnessed significant developments in the resolution of genetically encoded biosensors for single cell Ca2+ and cAMP measurements. In addition to their improved stability, dynamic range and signal-to-noise ratio, these sensors can also be targeted to discrete regions of the cell [45,46]. This has marked the beginning of a new era of Ca2+ and cAMP research in which we can begin to monitor the spatiotemporal dynamics of these diffusible messengers within specific cellular compartments. Sensor targeting has also been taken one step further by attaching sensors for Ca2+ and cAMP directly to specific AC isoforms to monitor signalling events within the immediate vicinity of cAMP production (Figure 2) [47,48]. This has provided a unique opportunity to identify key signalling components within AC microdomains and to establish the contributory roles of such components to the local dynamic signalling events.

Targeting of Ca2+ and cAMP sensors to the AC8 microdomain

Figure 2
Targeting of Ca2+ and cAMP sensors to the AC8 microdomain

(A) The high-affinity Ca2+ sensor GCaMP2 is tethered to the N-terminus of AC8, producing GCaMP2–AC8. GCaMP2 contains CaM, a circularly permuted green fluorescent protein (cpGFP) and CaM-binding peptide from myosin light chain kinase (M13). When Ca2+ levels increase, the CaM binds Ca2+ and interacts with the M13 peptide resulting in a conformational change in cpGFP and an increase GFP signal. (B) The FRET-based cAMP sensor Epac2-camps is attached to the N-terminus of AC8. This sensor consists of CFP (cyan fluorescent protein; donor fluorophore), Epac2 (exchange protein directly activated by cAMP 2) cyclic-nucleotide-binding domain (CBD) and YFP (yellow fluorescent protein; acceptor fluorophore). An increase in cAMP results in a conformational change in the CBD and a decrease in FRET between CFP and YFP. Both sensors are attached to AC8 via short linker peptides (broken line).

Figure 2
Targeting of Ca2+ and cAMP sensors to the AC8 microdomain

(A) The high-affinity Ca2+ sensor GCaMP2 is tethered to the N-terminus of AC8, producing GCaMP2–AC8. GCaMP2 contains CaM, a circularly permuted green fluorescent protein (cpGFP) and CaM-binding peptide from myosin light chain kinase (M13). When Ca2+ levels increase, the CaM binds Ca2+ and interacts with the M13 peptide resulting in a conformational change in cpGFP and an increase GFP signal. (B) The FRET-based cAMP sensor Epac2-camps is attached to the N-terminus of AC8. This sensor consists of CFP (cyan fluorescent protein; donor fluorophore), Epac2 (exchange protein directly activated by cAMP 2) cyclic-nucleotide-binding domain (CBD) and YFP (yellow fluorescent protein; acceptor fluorophore). An increase in cAMP results in a conformational change in the CBD and a decrease in FRET between CFP and YFP. Both sensors are attached to AC8 via short linker peptides (broken line).

The first direct measurements of Ca2+ changes within the AC8 microdomain were obtained using GCaMP2–AC8, a sensor in which the high-affinity Ca2+ sensor GCaMP2 was tethered to the N-terminus of a fully functional AC8 [48]. Consistent with earlier indications, GCaMP2–AC8 measurements confirmed that AC8 is exposed to large rapid increases in Ca2+ as a consequence of SOCC activation, but the AC is apparently ‘shielded’ from the significant cytosolic Ca2+ rises seen during Ins(1,4,5)P3-mediated store release or non-specific ionophore-mediated Ca2+ entry [48]. This demonstration of the residence of AC8 in a discrete SOCE-selective Ca2+ microdomain was nicely contrasted by GCaMP2–AC2 data showing that the non-raft-targeted AC2 is exposed to delayed Ca2+ increases during SOCE, but much larger Ca2+ increases during Ca2+ mobilization from ER stores and ionomycin treatment [48]. Thus it would appear that Ca2+-sensitive and Ca2+-insensitive ACs reside in very different Ca2+ microdomains. Consistent with earlier studies on AC6 [16], the Ca2+ signal detected by GCaMP2–AC8 was abolished by BAPTA, but was largely unaffected by the slower Ca2+ chelator EGTA [48].

Using the GCaMP2–AC8 signal as a read-out for the contribution of Orai1 to Ca2+ changes within the AC8 microdomain, we can now confirm a clear dependence of the SOCE-mediated signal on the direct association between AC8 and Orai1 (D. Willoughby, M.L. Halls, K.L. Everett, J. Pacheco, P. Skroblin, L. Vaca, E. Klussmann and D.M.F. Cooper, unpublished work). In parallel studies using Epac2-camps–AC8 (the FRET-based cAMP sensor Epac2-camps is tethered to the N-terminus of AC8 [47]), we demonstrated a direct dependence of AC8 activity on its ability to bind Orai1. It appears that this direct protein–protein interaction also contributes to the targeting of AC8 to the unique Ca2+ microdomain that reinforces it selective regulation by SOCE. It is yet to be established whether the interaction between AC8 and Orai1 is evident in excitable cells. This is an intriguing consideration, as recent findings reveal an inhibitory action of Orai1's binding partner, STIM1, on neuronal Ca2+ channels, mediated by a direct protein–protein interaction that can dictate whether Ca2+ entry proceeds via VGCCs or SOCCs [49,50].

Summary

Appreciation of the ability of signalling proteins to act as part of multiprotein signalling complexes targeted to specific sites within the cell in order to function with high specificity is rapidly gaining pace. One area of biology that has seen considerable advances following this realization is the field of cAMP signalling. The present review details a number of newly identified interacting partners for the Ca2+-regulated AC isoforms, including a selective interaction with Orai1, the pore-forming subunit of SOCCs. Identification of this direct protein–protein interaction goes a long way to explaining the well-established observation that these ACs are highly selective for SOCE over other types of Ca2+ rise.

Coupled with evidence of direct associations between the Ca2+-regulated ACs and other scaffold or signalling proteins (e.g. AKAP79 and PP2A), it is becoming apparent that the ACs are by no means solitary proteins, but act as central components of much larger signalling complexes. These macromolecular complexes serve to target cAMP-mediated events to precise locations within the cell. By combining the use of modern biochemical techniques and high-resolution fluorescence imaging with targeted biosensors, we can now begin to dissect out the key regulatory components shaping cAMP production by specific AC isoforms, and identify the downstream consequences of such events. Findings from such studies will provide important insights into the physiological roles played by specific ACs in cells expressing multiple AC isoforms.

Signalling 2011: a Biochemical Society Centenary Celebration: A Biochemical Society Focused Meeting held at the University of Edinburgh, U.K., 8–10 June 2011. Organized and Edited by Nicholas Brindle (Leicester, U.K.), Simon Cook (The Babraham Institute, U.K.), Jeff McIlhinney (Oxford, U.K.), Simon Morley (University of Sussex, U.K.), Sandip Patel (University College London, U.K.), Susan Pyne (University of Strathclyde, U.K.), Colin Taylor (Cambridge, U.K.), Alan Wallace (AstraZeneca, U.K.) and Stephen Yarwood (Glasgow, U.K.).

Abbreviations

     
  • AC

    adenylate cyclase

  •  
  • AKAP

    A-kinase-anchoring protein

  •  
  • BAPTA

    1,2-bis-(o-aminophenoxy)ethane-N,N,N′,N′-tetra-acetic acid

  •  
  • CaM

    calmodulin

  •  
  • ER

    endoplasmic reticulum

  •  
  • FRET

    fluorescence resonance energy transfer

  •  
  • HEK

    human embryonic kidney

  •  
  • PDE

    phosphodiesterase

  •  
  • PKA

    protein kinase A

  •  
  • PP2A

    protein phosphatase 2A

  •  
  • SERCA

    sarcoplasmic/endoplasmic reticulum Ca2+-ATPase

  •  
  • SOCC

    store-operated Ca2+ channel

  •  
  • SOCE

    store-operated Ca2+ entry

  •  
  • STIM1

    stromal interaction molecule 1

  •  
  • VGG

    voltage-gated Ca2+ channel

Funding

This work was supported by the Wellcome Trust.

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