© 1997 American Heart Association, Inc.
Articles |
C2 Region–Derived Peptides of ß-Protein Kinase C Regulate Cardiac Ca2+ Channels
From the Cardiology Division (Z.-H.Z., L.C., N.E.-S., M.B.), Department of Medicine, State University of New York, Health Science Center, and the Veterans Administration Medical Center, Brooklyn, New York, and the Department of Molecular Pharmacology (J.A.J., D.M.-R.), Stanford (Calif) University School of Medicine.
Correspondence to Dr Mohamed Boutjdir, Cardiology Division (IIIA), VA Medical Center, 800 Poly Place, Brooklyn, NY 11209. E-mail boutjdir.mohamed{at}brooklyn.va.gov
Abstract We have previously shown that
1-adrenergic activation inhibited
ß-adrenergic–stimulated L-type Ca2+ current
(ICa). To determine the role of protein kinase C
(PKC) in this regulation, the inositol trisphosphate pathway was
bypassed by direct activation of PKC with 4ß-phorbol
12-myristate 13-acetate (PMA). To minimize
Ca2+-induced Ca2+ inactivation,
Ba2+ current (IBa) was recorded
through Ca2+ channels in adult rat ventricular
myocytes. We found that PMA (0.1 µmol/L) consistently
inhibited basal IBa by 40.5±7.4% and
isoproterenol (ISO, 0.1 µmol/L)–stimulated
IBa by 48.9±7.8%. These inhibitory
effects were not observed with the inactive phorbol ester analogue
-phorbol 12,13-didecanoate (0.1 µmol/L). To identify the PKC
isozymes that mediate these PMA effects, we intracellularly applied
peptide inhibitors of a subclass of PKC isozymes, the
C2-containing cPKCs. These peptides (ßC2-2 and ßC2-4) specifically
inhibit the translocation and function of C2-containing isozymes
(-PKC, ßI-PKC, and ßII-PKC), but not the
C2-less isozymes (
-PKC and 
-PKC). We first used the
pseudosubstrate peptide (0.1 µmol/L in the pipette), which
inhibits the catalytic activity of all the PKC isozymes, and found that
PMA-induced inhibition of ISO-stimulated IBa was
reduced to 16.8±7.4% but was not affected by the scrambled
pseudosubstrate peptide. The effects of PMA on basal and ISO-stimulated
IBa were then determined in the presence of
C2-derived peptides or control peptides. When the pipette contained
0.1 µmol/L of ßC2-2 or ßC2-4, PMA-induced inhibition of
basal IBa was 26.1±4.5% and 23.6±2.2%,
respectively. Similarly, ISO-stimulated IBa was
inhibited by 29.9±6.6% and 29.3±7.8% in the presence of ßC2-2 and
ßC2-4, respectively. In contrast, there was no significant change in
the effect of PMA in the presence of control peptides, scrambled
ßC2-4, or pentalysine. Finally, PMA-induced inhibition of basal and
ISO-stimulated IBa was almost completely
abolished in cells dialyzed with both ßC2-2 and ßC2-4. Together,
these data suggest a role for C2-containing isozymes in mediating
PMA-induced inhibition of L-type Ca2+ channel activity.
Key Words: Ca2+ current • receptor • phorbol ester • protein kinase C isozyme • cardiac myocyte
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