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Unique modulation of L-type Ca²⁺ channels by short auxiliary _1d subunit present in cardiac muscle

Departments of ¹Medicine and ²Physiology, University of Wisconsin, Madison, Wisconsin; and ³Department of Pharmacology, University of Iowa, Iowa City, Iowa

Submitted 12 April 2004 ; accepted in final form 21 December 2004

Recent studies have identified a growing diversity of splice variants of auxiliary Ca²⁺ channel Ca_v subunits. The Ca_v1d isoform encodes a putative protein composed of the amino-terminal half of the full-length Ca_v1 isoform and thus lacks the known high-affinity binding site that recognizes the Ca²⁺ channel ₁-subunit, the -binding pocket. The present study investigated whether the Ca_v1d subunit is expressed at the protein level in heart, and whether it exhibits any of the functional properties typical of full-length Ca_v subunits. On Western blots, an antibody directed against the unique carboxyl terminus of Ca_v1d identified a protein of the predicted molecular mass of 23 kDa from canine and human hearts. Immunocytochemistry and surface-membrane biotinylation experiments in transfected HEK-293 cells revealed that the full-length Ca_v1b subunit promoted membrane trafficking of the pore-forming _1C (Ca_v1.2)-subunit to the surface membrane, whereas the Ca_v1d subunit did not. Whole cell patch-clamp analysis of transfected HEK-293 cells demonstrated no effect of coexpression of the Ca_v1d with the _1C-subunit compared with the 15-fold larger currents and leftward shift in voltage-dependent activation induced by full-length Ca_v1b coexpression. In contrast, cell-attached patch single-channel studies demonstrated that coexpression of either Ca_v1b or Ca_v1d significantly increased mean open probability four- to fivefold relative to the _1C-channels alone, but only Ca_v1b coexpression increased the number of channels observed per patch. In conclusion, the Ca_v1d isoform is expressed in heart and can modulate the gating of L-type Ca²⁺ channels, but it does not promote membrane trafficking of the channel complex.

electrophysiology; ion; heart; splice variant

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