Cardiac-specific overexpression of the alpha(1) subunit of the L-type voltage-dependent Ca(2+) channel in transgenic mice. Loss of isoproterenol-induced contraction.
The L-type voltage-dependent calcium channel (L-VDCC) regulates calcium influx in cardiac myocytes. Activation of the beta-adrenergic receptor (betaAR) pathway causes phosphorylation of the L-VDCC and that in turn increases Ca(2+) influx. Targeted expression of the L-VDCC alpha(1) subunit in transgenic (Tg) mouse ventricles resulted in marked blunting of the betaAR pathway. Inotropic and lusitropic responses to isoproterenol and forskolin in Tg hearts were significantly reduced. Likewise, Ca(2+) current augmentation induced by iso- proterenol and forskolin was markedly depressed in Tg cardiomyocytes. Despite no change in betaAR number, isoproterenol-stimulated adenylyl cyclase activity was absent in Tg membranes and NaF and forskolin responses were reduced. We postulate an important pathway for regulation of the betaAR by Ca(2+) channels.
Institute of Molecular Pharmacology and Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
J N
JN
Muth
H
H
Yamaguchi
G
G
Mikala
I L
IL
Grupp
W
W
Lewis
H
H
Cheng
L S
LS
Song
E G
EG
Lakatta
G
G
Varadi
A
A
Schwartz
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics*; D020864:Calcium Channels, N-Type; D005576:Colforsin / Q000494:pharmacology; D004452:Echocardiography; D005260:Female; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology*; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D000262:Adenylyl Cyclases; D002118:Calcium; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D005576:Colforsin; D007545:Isoproterenol; D046911:Macromolecular Substances; D011943:Receptors, Adrenergic, beta