Single-channel gating and regulation of human L-type calcium channels in cardiomyocytes of transgenic mice.
Overexpression of human cardiac L-type Ca(2+) channel pores (hCa(v)1.2) in mice causes heart failure. Earlier studies showed Ca(v)1.2-mRNA increase by 2.8-fold, but whole-cell current density enhancement by </=1.5-fold only. Three possible explanations were examined: (1) poor translation of hCa(v)1.2 and of its accessory subunits, (2) altered sarcolemmal insertion of functional channels, and (3) lower single-channel activity of overexpressed channels. Western blots revealed a 2.7-fold increase of Ca(v)1.2 protein in transgenic myocytes, but less enhanced expression of beta(1a) and beta(1b) subunits. beta(2) and alpha(2)/delta were significantly lowered. Density of functional channels was increased by 3.0-fold. Single-channel gating was impaired in transgenic cardiomyocytes: open probability and ensemble average currents were reduced by 60%. Furthermore, channels of transgenic myocytes were not stimulated by 8-Br-cAMP, in contrast to wild-types. Expression of malcomposed, dysfunctional L-type Ca(2+) channels in murine cardiomyocytes overexpressing hCa(v)1.2 explains the moderate enhancement of whole-cell currents and illustrates compensatory mechanisms in a transgenic disease model.
Groner
Ferdi
F
Department of Pharmacology, University of Cologne, 50931, Köln, Germany.
Rubio
Marta
M
Schulte-Euler
Patrick
P
Matthes
Jan
J
Khan
Ismail F Y
IF
Bodi
Ilona
I
Koch
Sheryl E
SE
Schwartz
Arnold
A
Herzig
Stefan
S
D000818:Animals; D015153:Blotting, Western; D020746:Calcium Channels, L-Type / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D004594:Electrophysiology; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000502:physiology*; D019319:Okadaic Acid / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D021122:Protein Subunits
D020746:Calcium Channels, L-Type; D021122:Protein Subunits; D019319:Okadaic Acid; D000242:Cyclic AMP