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(Circulation Research. 2002;90:369.)
© 2002 American Heart Association, Inc.

Editorials

Gaining Respectability

Membrane-Delimited, Caveolar-Restricted Activation of Ion Channels

Olivier Feron, Ralph A. Kelly

From the Unit of Pharmacology and Therapeutics (O.F.), Department of Medicine, University of Louvain Medical School, Brussels, Belgium; and Genzyme Corporation (R.A.K.), Cambridge, Mass.

Correspondence to Olivier Feron, University of Louvain Medical School, Unit of Pharmacology and Therapeutics, UCL-FATH 5349, 53, Avenue E. Mounier, B-1200 Brussels, Belgium. E-mail feron@mint.ucl.ac.be

Key Words: caveolae • caveolin • sodium channels • ß-adrenergic • G_s

Voltage-gated sodium channels play a key role in the excitability of myocardial cells and in impulse propagation.^1,2 An increase in Na⁺ current is, for example, responsible for the generation of the rapid upstroke of the action potential (phase 0). Mutations in the gene encoding this channel (SCN5A) have been linked to the pathogenesis of several cardiac channelopathies, including the long-QT and the Brugada syndromes,^1,2 the discoveries of which have helped in the functional characterization of these channels. In addition, the signaling pathways that regulate Na⁺ channel activity, such as the sympathetic nervous system, have been the subject of numerous studies.^3–6 Indeed, stimulation of ß-adrenergic receptors can both enhance conduction in normal ventricular myocardium but also induce arrhythmic events in a number of cardiac disease states.^1,2

Several mechanisms that contribute to the regulation of Na⁺ channels by ß-adrenergic stimulation have been documented (see Figure). All of them involve G proteins, although diffusible second messengers are not necessarily involved. For example, besides the coupling of G_s to adenylate cyclase and downstream protein kinase A (PKA)-mediated phosphorylation events,^3,4 the so-called "membrane-delimited" pathway does not involve diffusible cytosolic factors. The G_s subunit can, indeed, directly modify Na⁺ channel activity.^5,6 This type of regulation is not unique to G_s, as the direct binding of the Gß protein subunit to several Ca²⁺, K⁺, and Cl^- channels has been extensively documented (for review, see Dascal⁷).

View larger version (15K): [in this window] [in a new window]   Schematic representation f the 2 major pathways regulating voltage-dependent Na+ channels (Na+Ch) in cardiac . . . [Full Text of this Article]

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