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Dermot Cooper"Adenylyl cyclases and the organization of signalling microdomains"

Abstract :


Adenylyl cyclases are central regulators of most significant physiological processes – neuronal and non-neuronal.
Consequently, we should not be surprised that a wide range of cellular devices are in place to control both the generation and destruction of the signal, cAMP. My interest is concentrated on the regulation of Calcium-sensitive adenylyl cyclases (ACs). These enzymes are centrally placed to control neurotransmitter and hormone release, neuronal plasticity, learning and memory, cardiac rhythmicity etc. Their regulation by Ca2+ is their key regulatory feature and we focus on understanding how this occurs. It turns out that not alone are the enzymes regulated by Ca2+ or calmodulin by elegant biochemical mechanisms, there are also layers of sophisticated devices to ensure that the ACs respond selectively to some Ca2+-signals and not others. Our studies have revealed for instance that ACs are placed in dynamic domains of the cell known as lipid rafts in which they can associate with other key elements; they recruit the actin cytoskeleton; they also bind to the channels (Orai1) that regulate them in non-excitable cells. It is not yet proven if they can physically bind other channel elements in neurons. Using targeted sensors for both cAMP and Ca2+ it is clear that the cellular domains of the enzymes are ‘privileged regions’ where highly orchestrated signalling occurs. Thus we now view adenylyl cyclases as signalling hubs whose composition can be dynamic, regulated and region-specific. Awareness of these issues is vital to understanding the roles of cAMP and adenylyl cyclases.



Keywords:
Cellular signalling, cancer, adenylyl cyclase, protein kinase, cyclic AMP, AKAP, Akinase anchoring proteins

Selected publications

Organization and Ca2+ regulation of adenylyl cyclases in cAMP microdomains. Willoughby, D and Cooper, DMF. Physiological Reviews 87, 965-1010 (2007)

Direct demonstration of discrete Ca2+ microdomains associated with different adenylyl cyclase isoforms. D Willoughby, S Wachten, N Masada & DMF Cooper J Cell Science 123, 107-117 (2010)

Sub-picomolar relaxin signaling by a pre-assembled RXFP1, AKAP-79, AC2, β-arrestin 2, PDE4D3 complex. ML Halls and DMF Cooper EMBO Journal 29, 2772-2787 (2010)

Adenylyl cyclase AC8 directly controls its micro-environment by recruiting the actin cytoskeleton in a cholesterol-rich milieu. LJ Ayling, SJ Briddon, ML Halls, GRV Hammond, L Vaca, J Pacheco, SJ Hill and DMF Cooper J. Cell Sci. 125 869-886 (2012)

Direct binding of AC8 and Orai1 underlies dynamic Ca2+-regulated cAMP signalling. D Willoughby, KL Everett, ML Halls, J Pacheco, P Skroblin, L Vaca, E Klussmann and DMF Cooper Science Signaling (2012) 5, ra29

Françoise Coussen de l'IINS