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

L-Type calcium channels are multiprotein complexes composed of pore-forming ( Ca(V)1.2) and modulatory auxiliary alpha(2)delta- and beta-subunits. We demonstrate expression of two different isoforms for the beta(2)-subunit (beta(2a), beta(2b)) and the beta(3)-subunit (beta(3a), beta(3trunc)) in human non-failing and failing ischemic myocardium. Quantitatively, in the left ventricle expression of beta(2b) transcripts prevails in the order of > beta(3) >> beta(2a). The expressed cardiac full-length beta(3)-subunit is identical to the beta(3a)- isoform, and beta(3trunc) results from deletion of exon 6 ( 20 nn) entailing a reading frameshift and translation stop at nucleotide position 495. In failing ischemic myocardium beta(3trunc) expression increases whereas overall beta(3) expression remains unchanged. Heterologous coexpression studies demonstrated that beta(2) induced larger currents through rabbit and human cardiac Ca(V)1.2 pore subunits than beta(3) isoforms. All beta-subunits increased channel availability at single channel level, but beta(2) exerted an additional, marked stimulation of rapid gating ( open and closed times, first latency), leading to higher peak current values. We conclude that cardiac beta-subunit isoforms differentially modulate calcium inward currents because of regulatory effects within the channel protein complex. Moreover, differences in the various beta-subunit gene products present in human heart might account for altered single channel behavior found in human heart failure.