Why and When Your Next Heartbeat Will Occur

Abstract

Cardiac pacemaker cell automaticity is regulated by molecular self-organization within a coupled system of a chemical oscillators (“Ca2+ clock”), comprised of Ca2+ and other ion cycling molecules, and ion current oscillators, comprised of an ensemble of electrogenic molecules (surface membrane or “M clock”). Both Ca2+ and M clock molecules are activated by Ca2+ and voltage cues, that also oscillate within an AP cycle. CAMP, cAMP-mediated PKA and CAMKII-dependent phosphorylation modulate the availability of clock molecules to respond these activation cues. A crucial Ca2+ clock member, the sarcoplasmic reticulum (SR), functions as a Ca2+ capacitor, pumping Ca2+ via SERCA2 and releasing Ca via ryanodine receptors, (RyR). Spontaneous RyR activation becomes evident near the time at which maximum diastolic membrane potential (MDP) is achieved, and generates sub-sarcolemmel local Ca2+ releases that organize to activate INCX. The resultant induction of slow membrane depolarization activates low-voltage-activated Ca2+ channels that continues the feed-forward driven self-organization of coupled-clock functions to further accelerate the rate of diastolic VM depolarization. When the extent of depolarization of the system reaches a critical level, L-Type Ca2+ channels activate, effecting an abrupt and marked acceleration of VM depolarization that forms the rapid upstroke of the spontaneous AP. Concurrent influx via Ca replenishes intracellular Ca2+ to balance Ca efflux via NCX; VM depolarization and an increase in intracellular Ca2+ during the AP activate a family of K channels, leading to VM repolarization, which, in turn increases availability of NCX and HCN channel molecules for subsequent reactivation. Following re-achievement of the MDP, self-organization of functions within the coupled-clock system is reiterated to drive ensuing AP cycles. Thus, your heartbeat occurs when self-organization of a system of chemical and current oscillators that slowly depolarized VM achieves criticality, i.e. the VM required to launch the next AP.