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Choreographing the adenylyl cyclase signalosome: sorting out the partners and the steps

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Abstract

Adenylyl cyclases are a ubiquitous family of enzymes and are critical regulators of metabolic and cardiovascular function. Multiple isoforms of the enzyme are expressed in a range of tissues. However, for many processes, the adenylyl cyclase isoforms have been thought of as essentially interchangeable, with their impact more dependent on their common actions to increase intracellular cyclic adenosine monophosphate content regardless of the isoform involved. It has long been appreciated that each subfamily of isoforms demonstrate a specific pattern of “upstream” regulation, i.e., specific patterns of ion dependence (e.g., calcium-dependence) and specific patterns of regulation by kinases (protein kinase A (PKA), protein kinase C (PKC), raf). However, more recent studies have suggested that adenylyl cyclase isoform-selective patterns of signaling are a wide-spread phenomenon. The determinants of these selective signaling patterns relate to a number of factors, including: (1) selective coupling of specific adenylyl cyclase isoforms with specific G protein-coupled receptors, (2) localization of specific adenylyl cyclase isoforms in defined structural domains (AKAP complexes, caveolin/lipid rafts), and (3) selective coupling of adenylyl cyclase isoforms with specific downstream signaling cascades important in regulation of cell growth and contractility. The importance of isoform-specific regulation has now been demonstrated both in mouse models as well as in humans. Adenylyl cyclase has not been viewed as a useful target for therapeutic regulation, given the ubiquitous expression of the enzyme and the perceived high risk of off-target effects. Understanding which isoforms of adenylyl cyclase mediate distinct cellular effects would bring new significance to the development of isoform-specific ligands to regulate discrete cellular actions.

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Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

    Rennolds S. Ostrom & Amy S. Bogard

  2. Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada

    Robert Gros & Ross D. Feldman

  3. Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada

    Robert Gros & Ross D. Feldman

  4. Vascular Biology Research Group, Robarts Research Institute, University of Western Ontario, London, ON, Canada

    Robert Gros & Ross D. Feldman

  5. Robarts Research Institute, 100 Perth Dr. Stn B, P.O. Box 5015, London, ON, Canada, N6A 5K8

    Ross D. Feldman

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  1. Rennolds S. Ostrom
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  2. Amy S. Bogard
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  3. Robert Gros
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  4. Ross D. Feldman
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Correspondence to Ross D. Feldman.

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Ostrom, R.S., Bogard, A.S., Gros, R. et al. Choreographing the adenylyl cyclase signalosome: sorting out the partners and the steps. Naunyn-Schmiedeberg's Arch Pharmacol 385, 5–12 (2012). https://doi.org/10.1007/s00210-011-0696-9

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