Increased expression of the cardiac L-type calcium channel in estrogen receptor-deficient mice.
Steroid hormones control the expression of many cellular regulators, and a role for estrogen in cardiovascular function and disease has been well documented. To address whether the activity of the L-type Ca2+ channel, a critical element in cardiac excitability and contractility, is altered by estrogen and its nuclear receptor, we examined cardiac myocytes from male mice in which the estrogen receptor gene had been disrupted (ERKO mice). Binding of dihydropyridine Ca2+ channel antagonist isradipine (PN200-110) was increased 45.6% in cardiac membranes from the ERKO mice compared to controls, suggesting that a lack of estrogen receptors in the heart increased the number of Ca2+ channels. Whole-cell patch clamp of acutely dissociated adult cardiac ventricular myocytes indicated that Ca2+ channel current was increased by 49% and action potential duration was increased by 75%. Examination of electrocardiogram parameters in ERKO mice showed a 70% increase in the QT interval without significant changes in PQ or QRS intervals. These results show that the membrane density of the cardiac L-type Ca2+ channel is regulated by the estrogen receptor and suggest that decreased estrogen may lead to an increase in the number of cardiac L-type Ca2+ channels, abnormalities in cardiac excitability, and increased risk of arrhythmia and cardiovascular disease.
Johnson
B D
BD
Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, USA.
Zheng
W
W
Korach
K S
KS
Scheuer
T
T
Catterall
W A
WA
Rubanyi
G M
GM
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D004095:Dihydropyridines / Q000378:metabolism; D004558:Electric Stimulation; D004594:Electrophysiology; D017275:Isradipine / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011960:Receptors, Estrogen / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D008024:Ligands; D011960:Receptors, Estrogen; D014157:Transcription Factors; D017275:Isradipine