Review
Higher-order organization and regulation of adenylyl cyclases

https://doi.org/10.1016/j.tips.2006.06.002Get rights and content

There is increasing awareness of the compartmentalization of cAMP signalling – the means by which cAMP levels change in discrete domains of the cell with discrete local consequences. Current developments in understanding the organization of adenylyl cyclases in the plasma membrane are illuminating how the earliest part of cAMP compartmentalization could occur. This review focuses on recent findings regarding three levels of adenylyl cyclase organization – oligomerization, positioning to lipid rafts and participation in multiprotein signalling complexes. This organization, coupled with the role of scaffolding proteins in arranging the downstream effectors of cAMP, helps to identify complexes that greatly facilitate the translation of enzyme activation into local consequences.

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.

References (60)

  • T.J. Shuttleworth et al.

    Discriminating between capacitative and arachidonate-activated Ca2+ entry pathways in HEK293 cells

    J. Biol. Chem.

    (1999)
  • K.A. Fagan

    Regulation of the Ca2+-inhibitable adenylyl cyclase type VI by capacitative Ca2+ entry requires localization in cholesterol-rich domains

    J. Biol. Chem.

    (2000)
  • T.P. Lockwich

    Assembly of Trp1 in a signaling complex associated with caveolin-scaffolding lipid raft domains

    J. Biol. Chem.

    (2000)
  • R.S. Ostrom

    Receptor number and caveolar co-localization determine receptor coupling efficiency to adenylyl cyclase

    J. Biol. Chem.

    (2001)
  • V.O. Rybin

    Differential targeting of β-adrenergic receptor subtypes and adenylyl cyclase to cardiomyocyte caveolae. A mechanism to functionally regulate the cAMP signaling pathway

    J. Biol. Chem.

    (2000)
  • S. Schreiber

    A possible role for caveolin as a signaling organizer in olfactory sensory membranes

    J. Biol. Chem.

    (2000)
  • J.R. Martens

    Differential targeting of Shaker-like potassium channels to lipid rafts

    J. Biol. Chem.

    (2000)
  • A.J. Crossthwaite

    The cytosolic domains of Ca2+-sensitive adenylyl cyclases dictate their targeting to plasma membrane lipid rafts

    J. Biol. Chem.

    (2005)
  • O. Feron

    The endothelial nitric-oxide synthase–caveolin regulatory cycle

    J. Biol. Chem.

    (1998)
  • N. Mons et al.

    Adenylate cyclases: critical foci in neuronal signaling

    Trends Neurosci.

    (1995)
  • T.Y. Gao

    Complexes of the α1C and β subunits generate the necessary signal for membrane targeting of class C L-type calcium channels

    J. Biol. Chem.

    (1999)
  • T. Lockwich

    Stabilization of cortical actin induces internalization of transient receptor potential 3 (Trp3)-associated caveolar Ca2+ signaling complex and loss of Ca2+ influx without disruption of Trp3–inositol trisphosphate receptor association

    J. Biol. Chem.

    (2001)
  • Z. Wu

    Modification of the calcium and calmodulin sensitivity of the type I adenylyl cyclase by mutagenesis of its calmodulin binding domain

    J. Biol. Chem.

    (1993)
  • C. Gu et al.

    Calmodulin-binding sites on adenylyl cyclase type VIII

    J. Biol. Chem.

    (1999)
  • J.L. Chou

    Regulation of type VI adenylyl cyclase by Snapin, a SNAP25-binding protein

    J. Biol. Chem.

    (2004)
  • N. Lavine

    G protein-coupled receptors form stable complexes with inwardly rectifying potassium channels and adenylyl cyclase

    J. Biol. Chem.

    (2002)
  • A. Benians

    Regulators of G-protein signaling form a quaternary complex with the agonist, receptor, and G-protein. A novel explanation for the acceleration of signaling activation kinetics

    J. Biol. Chem.

    (2005)
  • F. Rochais

    Negative feedback exerted by cAMP-dependent protein kinase and cAMP phosphodiesterase on subsarcolemmal cAMP signals in intact cardiac myocytes: an in vivo study using adenovirus-mediated expression of CNG channels

    J. Biol. Chem.

    (2004)
  • R.S. Ostrom

    Nitric oxide inhibition of adenylyl cyclase type 6 activity is dependent upon lipid rafts and caveolin signaling complexes

    J. Biol. Chem.

    (2004)
  • W. Wong et al.

    AKAP signalling complexes: focal points in space and time

    Nat. Rev. Mol. Cell Biol.

    (2004)
  • Cited by (126)

    • Adenylyl cyclase 3 regulates osteocyte mechanotransduction and primary cilium

      2021, Biochemical and Biophysical Research Communications
    • Molecular features of adenylyl cyclase isoforms and cAMP signaling: A link between adenylyl cyclase 7 and depression

      2021, The Neuroscience of Depression: Genetics, Cell Biology, Neurology, Behavior, and Diet
    View all citing articles on Scopus
    View full text