Abstract
l-Type calcium channels are multiprotein complexes composed of pore-forming (CaV1.2) and modulatory auxiliary alpha2delta- and beta-subunits. We demonstrate expression of two different isoforms for the beta2-subunit (beta2a, beta2b) and the beta3-subunit (beta3a, beta3trunc) in human non-failing and failing ischemic myocardium. Quantitatively, in the left ventricle expression of beta2b transcripts prevails in the order of > beta3 >> beta2a. The expressed cardiac full-length beta3-subunit is identical to the beta3a-isoform, and beta3trunc results from deletion of exon 6 (20 nn) entailing a reading frameshift and translation stop at nucleotide position 495. In failing ischemic myocardium beta3trunc expression increases whereas overall beta3 expression remains unchanged. Heterologous coexpression studies demonstrated that beta2 induced larger currents through rabbit and human cardiac CaV1.2 pore subunits than beta3 isoforms. All beta-subunits increased channel availability at single channel level, but beta2 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.
Highlights
L-Type calcium channels are multiprotein complexes composed of pore-forming (CaV1.2) and modulatory auxiliary ␣2␦- and -subunits
Because truncated proteins may play a role in cardiomyopathy, as demonstrated for troponin I [24], we further investigated thephysiological relevance of 3trunc by performing RT-PCR experiments using primers 1 ϩ 2 (Fig. 1B) in left ventricular (LV) mRNA isolated from NF and ischemic cardiomyopathy (ICM) (Fig. 1C)
From human non-failing and failing ischemic cardiomyopathy whereas the 2b-specific probe hybridized to a major transcript of 9.5 kb in both specimens
Summary
L-Type calcium channels are multiprotein complexes composed of pore-forming (CaV1.2) and modulatory auxiliary ␣2␦- and -subunits. Heterologous coexpression studies demonstrated that 2 induced larger currents through rabbit and human cardiac CaV1.2 pore subunits than 3 isoforms.
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