Cardiac L-type calcium channel β-subunits expressed in human heart have differential effects on single channel characteristics

Abstract

L-Type calcium channels are multiprotein complexes composed of pore-forming (Cav1.2) and modulatory auxiliary α2δ- and β-subunits. We demonstrate expression of two different isoforms for the β2-subunit (β2a, β2b) and the β3-subunit (β3a, β3trunc) in human non-failing and failing ischemic myocardium. Quantitatively, in the left ventricle expression of β2b transcripts prevails in the order of > β3 ≫ β2a. The expressed cardiac full-length β3-subunit is identical to the β3a-isoform, and β3trunc results from deletion of exon 6 (20 nn) entailing a reading frameshift and translation stop at nucleotide position 495. In failing ischemic myocardium β3trunc expression increases whereas overall β3 expression remains unchanged. Heterologous coexpression studies demonstrated that β2 induced larger currents through rabbit and human cardiac Cav1.2 pore subunits than β3 isoforms. All β-subunits increased channel availability at single channel level, but β2 exerted an additional, marked stimulation of rapid gating (open and closed times, first latency), leading to higher peak current values. We conclude that cardiac β-subunit isoforms differentially modulate calcium inward currents because of regulatory effects within the channel protein complex. Moreover, differences in the various β-subunit gene products present in human heart might account for altered single channel behavior found in human heart failure.