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Protein kinase C activation inhibits Ca_v1.3 calcium channel at NH₂-terminal serine 81 phosphorylation site

¹Department of Cardiovascular Research, Veterans Affairs New York Harbor Healthcare System and Departments of Physiology and Pharmacology, Anatomy and Cell Biology, and Medicine, State University of New York Downstate Medical Center, Brooklyn, New York; ²Québec Heart Institute, Laval Hospital and Department of Medicine, Laval University, Sainte-Foy, Quebec, Canada; and ³Department of Medicine, New York University School of Medicine, New York, New York

Submitted 23 January 2006 ; accepted in final form 18 April 2006

The Ca_v1.3 (_1D) variant of L-type Ca²⁺ 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 _1D Ca²⁺ channel modulation by protein kinase C (PKC). Specifically, we show that the serine 81 (S81) phosphorylation site at the NH₂-terminal region plays a critical role in _1D Ca²⁺ 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 _1D Ca²⁺ channel. The modulation of _1D Ca²⁺ channel by PKC was prevented by dialyzing cells with a 35-amino acid peptide mimicking the _1D NH₂-terminal region comprising S81. In addition, the data revealed that only II- and PKC isozymes are implicated in this regulation. These novel findings have significant implications in the pathophysiology of _1D Ca²⁺ channel and in the development of PKC isozyme-targeted therapeutics.

calcium channels; protein kinase c isozymes; patch clamp