Background: Sinoatrial node cells (SANC) automaticity is generated by functional association between the activity of plasmalemmal ion channels and local diastolic intracellular Ca release (LCR) from ryanodine receptors. Strikingly, most isolated SANC exhibit a "dormant" state, whereas only a fraction shows regular firing as observed in intact SAN. Recent studies showed that β-adrenergic stimulation can initiate spontaneous firing in dormant SANC, though this mechanism is not entirely understood.
Methods: To investigate the role of L-type Ca1.3 Ca channels in the adrenergic regulation of automaticity in dormant SANC, we used a knock-in mouse strain in which the sensitivity of L-type Ca1.2 α1 subunits to dihydropyridines (DHPs) was inactivated (), enabling the selective pharmacological inhibition of Ca1.3 by DHPs.
Results: In dormant SANC, β-adrenergic stimulation with isoproterenol (ISO) induced spontaneous action potentials (AP) and Ca transients, which were completely arrested with concomitant perfusion of the DHP nifedipine. In spontaneously firing SANC at baseline, Ca1.3 inhibition completely reversed the effect of β-adrenergic stimulation on AP and the frequency of Ca transients. Confocal calcium imaging of SANC showed that the β-adrenergic-induced synchronization of LCRs is regulated by the activity of Ca1.3 channels.
Conclusions: Our study shows a novel role of Ca1.3 channels in initiating and maintaining automaticity in dormant SANC upon β-adrenergic stimulation.
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| http://dx.doi.org/10.3390/cells11071114 | DOI Listing |
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