Trends in Pharmacological Sciences
ReviewHigher-order organization and regulation of adenylyl cyclases
Introduction
Since its discovery 50 years ago, cAMP has been the prototypical second messenger, translating the actions of numerous extracellular effectors into consequences for virtually every aspect of cellular function. Among other signalling paradigms that were first developed from cAMP, such as those of G proteins and phosphorylation cascades, was the issue of compartmentalization – the concept whereby cAMP can be partitioned to discrete regions of the cell with numerous regulatory consequences. The pioneering work of Buxton and Brunton in cardiomyocytes was the first to provide compelling experimental evidence of the existence of compartmentalization as an essential feature in the action of cAMP, showing that adrenoceptor-mediated stimulation of adenylyl cyclase (AC) activates a particulate pool of protein kinase A (PKA), whereas prostaglandin (PG)E1 stimulation activates cytosolic PKA [1]. However, only relatively recently has it begun to be understood how a combination of protein–protein and protein–lipid interactions contributes to the manifestation of compartmentalization. From regulation by G-protein-coupled receptors (GPCRs) to activation of cAMP effectors and signal termination by phosphodiesterases (PDEs), the cAMP message is governed by sophisticated protein scaffolding systems that tailor the spatiotemporal aspect of the signal to produce a specific response. Much is known about how GPCRs, cAMP-dependent PKA, A-kinase-anchoring proteins (AKAPs) and PDEs are organized 2, 3, 4. By comparison, little is known about how the central controlling member of the cAMP cascade – AC – is organized. In this review, we summarize recent findings about ACs with regard to oligomeric assemblies, protein–lipid interactions and protein–protein interactions – which, together, define how ACs partake in higher-order signalling complexes and contribute to cAMP compartmentalization.
Section snippets
The transmembrane domains of ACs determine quaternary structure and plasma membrane targeting
The idea that ACs exist as single molecules at the plasma membrane is being superseded by the realization that dimerization or oligomerization is an essential feature in AC regulation. The longstanding puzzle behind the complex structure of ACs is beginning to be understood in terms of both internal intramolecular associations and intermolecular dimerization or hetero-oligomerization, which govern the formation of the AC catalytic core and regulate the trafficking of ACs to the plasma membrane.
The local membrane environment is a crucial determinant of AC regulation
Two general mechanisms organize proteins in signalling modules. The first relies on pre-existing physical interactions so that the signal is transmitted more or less instantaneously: for example, the association of PKA with its effectors by anchoring proteins of the AKAP family [2]. The second is a more passive mechanism that relies on signalling proteins being in close proximity but not in a pre-existing interacting complex. This arrangement increases the concentration of the reactants within
A current model of the incorporation of AC into cAMP signalling modules
The sulfonylurea (SU) receptor (as is the case with AC) is a member of the ABC superfamily of transporters that exists in a hetero-octameric complex with ATP-sensitive K+ channels (KATP channels). This complex enables the rapid conversion of metabolic signals into alterations in membrane potential. The KATP–SU-receptor complex serves as a model of how dimers or oligomers of the related ACs might participate in complexes with additional proteins [42], particularly voltage-gated Ca2+ channels and
Concluding remarks
ACs are re-emerging as central molecules that dictate the compartmentalization of the cAMP message. A complex interplay of intramolecular and intermolecular interactions governs the regulation of catalytic activity, trafficking, membrane localization and higher-order associations. The dimerization of ACs might be the key property that enables their incorporation into larger multimeric complexes and, in combination with isoform-specific regulators and plasma membrane compartmentalization, this
Update
A functional complex comprising AC, β2-adrenoceptor, PP2A, PKA and CaV1.2, similar to that described in hippocampal neurons [50], has recently been demonstrated in cardiomyocytes [60]. This report contained the additional findings that the AC involved is Ca2+ sensitive (AC5–AC6) and that the cAMP regulation of CaV1.2 is dependent on localization to caveolar microdomains.
Acknowledgements
We are very grateful to our colleague Agnes Martin for preparing the figures.
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