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Swimming regulations for protein kinase A catalytic subunit

Gold, M; (2019) Swimming regulations for protein kinase A catalytic subunit. Biochemical Society Transactions , 47 (5) pp. 1355-1366. 10.1042/BST20190230. Green open access

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Abstract

cAMP-dependent protein kinase (PKA) plays a central role in important biological processes including synaptic plasticity and sympathetic stimulation of the heart. Elevations of cAMP trigger release of PKA catalytic (C) subunits from PKA holoenzymes, thereby coupling cAMP to protein phosphorylation. Uncontrolled C subunit activity, such as occurs in genetic disorders in which regulatory subunits are depleted, is pathological. Anchoring proteins that associate with PKA regulatory subunits are important for localising PKA activity in cells. However, anchoring does not directly explain how unrestrained ‘free swimming' of C subunits is avoided following C subunit release. In this review, I discuss new mechanisms that have been posited to account for this old problem. One straightforward explanation is that cAMP does not trigger C subunit dissociation but instead activates intact PKA holoenzymes whose activity is restrained through anchoring. A comprehensive comparison of observations for and against cAMP-activation of intact PKA holoenzymes does not lend credence to this mechanism. Recent measurements have revealed that PKA regulatory subunits are expressed at very high concentrations, and in large molar excess relative to C subunits. I discuss the implications of these skewed PKA subunit concentrations, before considering how phosphorylation of type II regulatory subunits and myristylation of C subunits are likely to contribute to controlling C subunit diffusion and recapture in cells. Finally, I speculate on future research directions that may be pursued on the basis of these emerging mechanisms.

Type: Article
Title: Swimming regulations for protein kinase A catalytic subunit
Open access status: An open access version is available from UCL Discovery
DOI: 10.1042/BST20190230
Publisher version: https://doi.org/10.1042/BST20190230
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: anchoring, cAMP, protein kinase A, signalling
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10082131
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