The protein kinase A-regulated cardiac CI- channel resembles the cystic fibrosis transmembrane conductance regulator

Abstract

Stimulation of β-adrenoceptors in cardiac ventricular myocytes activates a strong chloride ion conductance1-5 as a result of phosphorylation by cyclic AMP-dependent protein kinase (PKA)2,4. This Cl- conductance, which is time- and voltage-independent 1,5, counters2,5 the tendency of the simultaneously enhanced Ca2+ channel current to prolong the ventricular action potential. Using inside-out giant patches6 excised from guinea-pig myocytes, we show here that phosphorylation by the PKA catalytic subunit plus Mg-ATP elicits discrete Cl- channel currents. In almost symmetrical Cl- solutions (∼150 mM), unitary current amplitude scales with membrane potential, and reverses sign near 0 mV, to yield a single channel conductance of ∼12 pS. Opening of the phosphorylated channels requires hydrolysable nucleoside triphosphate, indicating that phosphorylation by PKA is necessary, but not sufficient, for channel activation. The properties of these PKA-regulated cardiac Cl- channels are very similar, if not identical, to those of the cystic fibrosis transmembrane conductance regulator (CFTR)7, the epithelial cell Cl- channel whose regulation is defective in patients with cystic fibrosis. The full cardiological impact of these Cl- channels and of their possible malfunction in patients with cystic fibrosis remains to be determined. © 1992 Nature Publishing Group.