title: Moderate calcium channel dysfunction in adult mice with inducible cardiomyocyte-specific excision of the cacnb2 gene.
abstract: The major L-type voltage-gated calcium channels in heart consist of an α1C (Ca(V)1.2) subunit usually associated with an auxiliary β subunit (Ca(V)β2). In embryonic cardiomyocytes, both the complete and the cardiac myocyte-specific null mutant of Ca(V)β2 resulted in reduction of L-type calcium currents by up to 75%, compromising heart function and causing defective remodeling of intra- and extra-embryonic blood vessels followed by embryonic death. Here we conditionally excised the Ca(V)β2 gene (cacnb2) specifically in cardiac myocytes of adult mice (KO). Upon gene deletion, Ca(V)β2 protein expression declined by >96% in isolated cardiac myocytes and by >74% in protein fractions from heart. These latter protein fractions include Ca(V)β2 proteins expressed in cardiac fibroblasts. Surprisingly, mice did not show any obvious impairment, although cacnb2 excision was not compensated by expression of other Ca(V)β proteins or changes of Ca(V)1.2 protein levels. Calcium currents were still dihydropyridine-sensitive, but current density at 0 mV was reduced by <29%. The voltage for half-maximal activation was slightly shifted to more depolarized potentials in KO cardiomyocytes when compared with control cells, but the difference was not significant. In summary, Ca(V)β2 appears to be a much stronger modulator of L-type calcium currents in embryonic than in adult cardiomyocytes. Although essential for embryonic survival, Ca(V)β2 down-regulation in cardiomyocytes is well tolerated by the adult mice.
authors.affiliation: Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Meissner
authors.forename: Petra
authors.initials: P
authors.lastname: Weissgerber
authors.forename: Juan E Camacho
authors.initials: JE
authors.lastname: Londoño
authors.forename: Jean
authors.initials: J
authors.lastname: Prenen
authors.forename: Sabine
authors.initials: S
authors.lastname: Link
authors.forename: Sandra
authors.initials: S
authors.lastname: Ruppenthal
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Peter
authors.initials: P
authors.lastname: Lipp
authors.forename: Bernd
authors.initials: B
authors.lastname: Nilius
authors.forename: Marc
authors.initials: M
authors.lastname: Freichel
authors.forename: Veit
authors.initials: V
authors.lastname: Flockerzi
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000096:biosynthesis* / Q000235:genetics; D004622:Embryo, Mammalian / Q000201:enzymology / Q000473:pathology; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics
chemical_list: C491528:Cacnb2 protein, mouse; D020746:Calcium Channels, L-Type; D009124:Muscle Proteins