Abstract.
Dephosphorylation of the CFTR Cl– channel is known to be induced by both okadaic-acid- (OA-) sensitive and -insensitive protein phosphatases (PPs). In the present study, the effects of cytosolic free Mg2+ on the cardiac CFTR Cl– current were examined in relation to the latter PP activity in guinea pig ventricular myocytes. Even when maintaining intracellular Mg-ATP at millimolar concentrations under whole-cell patch-clamp mode, cAMP-activated Cl– conductance was reversibly suppressed by cytosolic free Mg2+, with an IC50 of around 2.5 mmol/l. In contrast, changes in the cytosolic concentration of free Mg2+ ([Mg2+]i) had no effect on genistein-activated CFTR Cl– currents. The Mg2+ effect on cAMP-activated CFTR Cl– conductance was completely reversed by application of anthracene-9-carboxylic acid (9-AC), which was previously shown to inhibit an OA-insensitive PP in cardiac myocytes. A 9-AC-sensitive fraction of endogenous PP activity in the extract of guinea pig ventricle was found to be activated by free Mg2+ at millimolar concentrations but to be inactive at micromolar concentrations. The intracellular application of OA failed to activate basal Cl– conductance at millimolar [Mg2+]i. In the presence of OA, however, basal Cl– conductance became activated either by reducing [Mg2+]i to micromolar concentrations or by applying 9-AC. Thus, we conclude that a Mg2+-dependent PP sensitive to 9-AC plays a key role in the cAMP-mediated regulation of cardiac CFTR Cl– channel at physiological [Mg2+]i under both basal and cAMP-activated conditions. Also, it appears that the genistein-activated conformation of the cardiac CFTR channel is not sensitive to the Mg2+-dependent PP.
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Zhou, SS., Takai, A. & Okada, Y. Regulation of cardiac CFTR Cl– channel activity by a Mg2+-dependent protein phosphatase. Pflügers Arch - Eur J Physiol 444, 327–334 (2002). https://doi.org/10.1007/s00424-002-0822-0
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DOI: https://doi.org/10.1007/s00424-002-0822-0