title: Single-channel gating and regulation of human L-type calcium channels in cardiomyocytes of transgenic mice.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Cologne, 50931, Köln, Germany.
authors.forename: Ferdi
authors.initials: F
authors.lastname: Groner
authors.forename: Marta
authors.initials: M
authors.lastname: Rubio
authors.forename: Patrick
authors.initials: P
authors.lastname: Schulte-Euler
authors.forename: Jan
authors.initials: J
authors.lastname: Matthes
authors.forename: Ismail F Y
authors.initials: IF
authors.lastname: Khan
authors.forename: Ilona
authors.initials: I
authors.lastname: Bodi
authors.forename: Sheryl E
authors.initials: SE
authors.lastname: Koch
authors.forename: Arnold
authors.initials: A
authors.lastname: Schwartz
authors.forename: Stefan
authors.initials: S
authors.lastname: Herzig
mesh_terms: 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
chemical_list: D020746:Calcium Channels, L-Type; D021122:Protein Subunits; D019319:Okadaic Acid; D000242:Cyclic AMP