Design of mutant beta2 subunits as decoy molecules to reduce the expression of functional Ca2+ channels in cardiac cells

The Journal of Pharmacology and Experimental Therapeutics
Sabine TélémaqueJames D Marsh

Abstract

Calcium influx through long-lasting ("L-type") Ca(2+) channels (Ca(V)) drives excitation-contraction in the normal heart. Dysregulation of this process contributes to Ca(2+) overload, and interventions that reduce expression of the pore-forming alpha(1) subunit may alleviate cytosolic Ca(2+) excess. As a molecular approach to disrupt the assembly of Ca(V)1.2 (alpha(1C)) channels at the cell membrane, we targeted the Ca(2+) channel beta(2) subunit, an intracellular chaperone that interacts with alpha(1C) via its beta interaction domain (BID) to promote Ca(V)1.2 channel expression. Recombinant adenovirus expressing either the full beta(2) subunit (Full-beta(2)) or truncated beta(2) subunit constructs lacking either the C terminus, N terminus, or both (N-BID, C-BID, and BID, respectively) fused to green fluorescent protein were developed as potential decoys and overexpressed in HL-1 cells. Fluorescence microscopy revealed that the localization of Full-beta(2) at the surface membrane was associated with increased Ca(2+) current mainly attributed to Ca(V)1.2 channels. In contrast, truncated N-BID and C-BID constructs showed punctate intracellular expression, and BID showed a diffuse cytosolic distribution. Total expression of the al...Continue Reading

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Citations

Feb 5, 2013·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Biny K JosephSung W Rhee
Oct 5, 2017·Journal of the American Heart Association·Jiaqi TangZhice Xu
Aug 28, 2012·Journal of Biomolecular Screening·Michael J Morton, Martin J Main
Oct 21, 2010·Physiological Reviews·Zafir Buraei, Jian Yang
Jan 1, 2013·ISRN Biochemistry·Nikolai M Soldatov
Aug 14, 2009·Expert Review of Cardiovascular Therapy·Sabine Telemaque, James D Marsh

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