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.
Highlights
The cardiac pacemaker is regulated by the surface membrane potential and changes in intracellular calcium levels, which are referred to as the membrane and calcium clocks, respectively
As Trimeric intracellular cation (TRIC) channels were estimated to affect calcium handling in the pacemaker cells in the sinus node, we analyzed the expression of TRIC-related molecules in the sinus node by reverse transcription polymerase chain reaction (RT-PCR) analyses
After ablation of the TRIC-A gene, there were no significant changes in TRIC-B expression, and TRIC-B haplodeficiency resulted in no significant changes in TRIC-A expression, suggesting that expression of each TRIC channel is regulated independently
Summary
The cardiac pacemaker is regulated by the surface membrane potential and changes in intracellular calcium levels, which are referred to as the membrane and calcium clocks, respectively. RyRs are expressed in excitable cells, such as the sinus node, and play major roles in calcium-induced calcium release (CICR) from intracellular calcium stores [2, 3]. Counterion movement due to trimeric intracellular cation (TRIC) channels located on the SR membrane in the sinus node is thought to balance this negative membrane potential, resulting in cancellation of electronic disturbance due to calcium release from RyRs [4]. As TRIC channels play a significant role in maintaining ion balance in the SR, they may modulate the calcium clock by affecting calcium-related ion currents in the sinus node. Which of the two known TRIC isoforms (TRIC-A and TRIC-B) plays a significant role in calcium movement in the sinus node is not known. The present study evaluated the importance of TRIC channels in the sinus node with genetically manipulated TRIC-A–/–and TRIC-B+/–mice
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