Journal
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
Volume 441, Issue 6, Pages 807-815Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s004240000485
Keywords
AKAP; CFTR; Cl- channel; Na+-K+ pump; protein kinase A; ventricular myocyte
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Protein-kinase-A- (PKA-) dependent regulation of cystic fibrosis transmembrane conductance regulator (CFTR) Cl- current (I-CFTR) and Na+-K+ pump current (I-p) was studied in single guinea-pig ventricular myocytes. Both currents were measured simultaneously by means of whole-cell recording at 30 degreesC. The adenylyl cyclase activator forskolin was used to stimulate PKA activity. At -20 mV, forskolin (4 muM) induced a fast activation of I-p, and a delayed stimulation of I-p. Despite the strikingly different time courses, however, the potency of the drug to regulate both currents was identical. Half-maximal activation of I,,, and stimulation of I-p respectively, were observed at 9.6x10(-8) M and 9.9x10(-8) M forskolin. Inclusion of a specific peptide inhibitor of PKA in the pipette solution (PKI, 20 muM) blocked forskolin's effect on I-p However, regardless of the time allowed for cell dialysis, there still was a marked, transient activation of I-CFTR which could be prevented by: (1) a short pre-activation of I-CFTR with forskolin or (2) the additional inclusion in the pipette solution of a synthetic peptide (Ht31 peptide, 60 CIM) that interferes with PKA binding to its anchoring proteins. Thus, there is a tight functional coupling between PKA and CFTR Cl- channels in guinea-pig ventricular myocytes. The coupling is probably due to the close physical proximity of channels and kinases mediated by PKA anchoring proteins. Na+-K+ pumps, on the other hand, though also regulated by PKA, appear to be loosely coupled to the kinases.
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