Cav3.1/α1G T-Type Ca2+ Channels are Involved in the Heart Rate Regulation

T-type Ca2+ channels (TTCCs) are expressed in cardiac pacemaker cells and conduction system of mammals. However, the role of TTCCs in heart rate (HR) generation and regulation is not well understood. In the mouse, the major TTCC expressed in the heart is Cav3.1/α1G, and therefore we used Cav3.1/α1G transgenic (TG) and knockout (KO) mice respectively to define the role of TTCC in the heart rate generation and regulation. Methods: Telemetric (conscious) and surface (anesthetized) ECG were used to determine the effect of isoproterenol (ISO) on the HR in vivo. To reduce the complication of in vivo HR regulation, Langendorff ECG was used to measure the response of the HR to ISO. Whole cell voltage clamp was used to measure the ICa-T before and after ISO application on TG myocytes. Results: At baseline, telemetric ECG recording showed no significant difference in HR between the Cav3.1/α1G TG mice (536.3±24.8bpm vs. FVB control: 550.6±15.3bpm), Cav3.1/α1G KO mice (614.4±39.9bpm vs. c57/bl6 control: 603.1±64.5bpm) and control mice was detected. ISO increased the HR rate in conscious mice to the same extent in both TG (41.2±6.9% vs. FVB control: 34.0±3.6%) and KO (22.6±8.8% vs. c57/bl6 control: 22.8±8.5%) mice. However, when the central regulation is depressed (anesthetized) or removed (ex-vivo Langendorff perfusion), the percentage of HR increase after ISO application were significantly enhanced in the TG mice but reduced in KO mice. Cav3.1/α1G T-type Ca2+ currents (ICa-T) in sinoatrial nodal cells was significantly increased by 43±16 % by ISO. Conclusions: Cav3.1/α1G TTCC might not play a major role in basal HR generation but it may play an important role in sympathetic/adrenergic regulation of HR, in which PKA could be an important mediator.