Involvement of Voltage-Dependent Ca²⁺ Channel β₃ Subunit in the Autonomic Control of Heart Rate Variability

Noradrenaline release from sympathetic nerve terminals is dependent on Ca²⁺ entry through neuronal voltage-gated N-type Ca²⁺ channels. The accessory β₃ subunits of Ca²⁺ channels (CaVβ₃) are preferentially associated with the α1B subunit to form N-type Ca²⁺ channels, and are therefore expected to play a functional role in the stimulation-evoked release of noradrenaline. In this study, we employed CaVβ₃-null, CaVβ₃-overexpressing (CaVβ₃-Tg), and wild-type (WT) mice to investigate the possible roles of CaVβ₃ in the sympathetic regulation of heart rate in vivo. Telemetry was used to monitor the ECG and both time and frequency domain analyses were carried out to evaluate heart rate variability. In the frequency domain analysis, power spectral density of the RR interval series was computed using the fast Fourier transform algorithm. The resting heart rate was increased in CaVβ₃-Tg mice compared with both CaVβ₃-null and WT mice. Mice overexpressing CaVβ₃ displayed decreased heart rate variability, which was measured by the time domain analysis of the standard deviation of RR intervals. In the frequency domain analysis, CaVβ₃-Tg mice showed decreased spectral powers compared with WT and CaVβ₃-null mice. Pharmacological blockade of β-adrenergic receptors with metoprolol decreased the heart rate in all genotypes, but the extent of the decrease was most obvious in CaVβ₃-Tg mice. On the other hand, the spectral powers were decreased in response to parasympathetic blockade (atropine) in WT and CaVβ₃-Tg mice. These results indicate the functional roles of CaVβ₃ in regulating sympathetic nerve signaling.