Cardiac L-type calcium channel beta-subunits expressed in human heart have differential effects on single channel characteristics.
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.
Hullin
Roger
R
Cardiology, Swiss Cardiovascular Heart Center Bern, University Hospital, 3010 Bern, Switzerland. roger.hullin@insel.ch
Khan
Ismail Friedrich Yunus
IF
Wirtz
Susanne
S
Mohacsi
Paul
P
Varadi
Gyula
G
Schwartz
Arnold
A
Herzig
Stefan
S
D000818:Animals; D015152:Blotting, Northern; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D003001:Cloning, Molecular; D006224:Cricetinae; D004594:Electrophysiology; D005091:Exons; D017353:Gene Deletion; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D009206:Myocardium / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D011994:Recombinant Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D015220:Calcium Channels; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D020033:Protein Isoforms; D012333:RNA, Messenger; D011994:Recombinant Proteins; D002118:Calcium