Protein kinase C activation inhibits Cav1.3 calcium channel at NH2-terminal serine 81 phosphorylation site.
The Ca(v)1.3 (alpha(1D)) variant of L-type Ca(2+) channels plays a vital role in the function of neuroendocrine and cardiovascular systems. In this article, we report on the molecular and functional basis of alpha(1D) Ca(2+) channel modulation by protein kinase C (PKC). Specifically, we show that the serine 81 (S81) phosphorylation site at the NH(2)-terminal region plays a critical role in alpha(1D) Ca(2+) channel modulation by PKC. The introduction of a negatively charged residue at position 81, by converting serine to aspartate, mimicked the PKC phosphorylation effect on alpha(1D) Ca(2+) channel. The modulation of alpha(1D) Ca(2+) channel by PKC was prevented by dialyzing cells with a 35-amino acid peptide mimicking the alpha(1D) NH(2)-terminal region comprising S81. In addition, the data revealed that only betaII- and epsilonPKC isozymes are implicated in this regulation. These novel findings have significant implications in the pathophysiology of alpha(1D) Ca(2+) channel and in the development of PKC isozyme-targeted therapeutics.
Baroudi
Ghayath
G
Veterans Affairs New York Harbor Healthcare System, Research and Development (151 800 Poly Place, Brooklyn, NY 11209, USA.
Qu
Yongxia
Y
Ramadan
Omar
O
Chahine
Mohamed
M
Boutjdir
Mohamed
M
D000595:Amino Acid Sequence; D000818:Animals; D015220:Calcium Channels / Q000032:analysis / Q000187:drug effects / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000032:analysis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D012694:Serine / Q000032:analysis / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
C472073:CACNA1D protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D007527:Isoenzymes; C093712:Cacna1d protein, rat; D012694:Serine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate