The protein kinase A-regulated cardiac Cl- channel resembles the cystic fibrosis transmembrane conductance regulator.
Stimulation of beta-adrenoceptors in cardiac ventricular myocytes activates a strong chloride ion conductance as a result of phosphorylation by cyclic AMP-dependent protein kinase (PKA). This Cl- conductance, which is time- and voltage-independent, counters the tendency of the simultaneously enhanced Ca2+ channel current to prolong the ventricular action potential. Using inside-out giant patches 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 (approximately 150 mM), unitary current amplitude scales with membrane potential, and reverses sign near 0 mV, to yield a single channel conductance of approximately 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), 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.
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D015152:Blotting, Northern; D018118:Chloride Channels; D002713:Chlorine / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D006160:Guanosine Triphosphate / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000502:physiology; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology*; D012313:RNA / Q000032:analysis; D011943:Receptors, Adrenergic, beta / Q000502:physiology
D018118:Chloride Channels; D008565:Membrane Proteins; D011943:Receptors, Adrenergic, beta; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002713:Chlorine; D012313:RNA; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D011494:Protein Kinases