Decreased cardiac pacemaking and attenuated β-adrenergic response in TRIC-A knockout mice

Abstract

Changes in intracellular calcium levels in the sinus node modulate cardiac pacemaking (the calcium clock). Trimeric intracellular cation (TRIC) channels are counterion channels on the surface of the sarcoplasmic reticulum and compensate for calcium release from ryanodine receptors, which play a major role in calcium-induced calcium release (CICR) and the calcium clock. TRIC channels are expected to affect the calcium clock in the sinus node. However, their physiological importance in cardiac rhythm formation remains unclear. We evaluated the importance of TRIC channels on cardiac pacemaking using TRIC-A-null (TRIC-A–/–) as well as TRIC-B+/–mice. Although systolic blood pressure (SBP) was not significantly different between wild-type (WT), TRIC-B+/–, and TRIC-A–/–mice, heart rate (HR) was significantly lower in TRIC-A–/–mice than other lines. Interestingly, HR and SBP showed a positive correlation in WT and TRIC-B+/–mice, while no such correlation was observed in TRIC-A–/–mice, suggesting modification of the blood pressure regulatory system in these mice. Isoproterenol (0.3 mg/kg) increased the HR in WT mice (98.8 ± 15.1 bpm), whereas a decreased response in HR was observed in TRIC-A–/–mice (23.8 ± 5.8 bpm), suggesting decreased sympathetic responses in TRIC-A–/–mice. Electrocardiography revealed unstable R-R intervals in TRIC-A–/–mice. Furthermore, TRIC-A–/–mice sometimes showed sinus pauses, suggesting a significant role of TRIC-A channels in cardiac pacemaking. In isolated atrium contraction or action potential recording, TRIC-A–/–mice showed decreased response to a β-adrenergic sympathetic nerve agonist (isoproterenol, 100 nM), indicating decreased sympathetic responses. In summary, TRIC-A–/–mice showed decreased cardiac pacemaking in the sinus node and attenuated responses to β-adrenergic stimulation, indicating the involvement of TRIC-A channels in cardiac rhythm formation and decreased sympathetic responses.