Rhythm and Rate of Action Potential Firing of Single Cardiac Pacemaker Cells Emerge from Concordant Beat to Beat Variability of Coupled Calcium and Membrane Potential Functions

Abstract

Bi-directional entrainment of surface membrane electrogenic proteins (“M-clock”) and intracellular sarcoplasmic reticulum Ca2+ cycling (Ca2+-clock) proteins regulates the mean action potential (AP) firing interval (APFI) of adult sinoatrial node cells (SANC). We hypothesized that not only the mean APFI but also APFI variability (APFIV) in any “steady state” are determined by concordant beat to beat variability of membrane potential and Ca2+ regulatory functions during an AP cycle. We tested this hypothesis in single, isolated adult rabbit SANC by measuring mean and beat to beat variability of Ca2+-clock functions (spontaneous diastolic local Ca2+ releases, kinetics of AP induced Ca2+-transient decay) and of M-clock functions (the kinetics of diastolic membrane depolarization and AP repolarization) across a broad range of “steady state” mean AP firing rates effected by autonomic receptor stimulation. A three-fold range of the mean APFI was accompanied by a four-fold range of APFIV. In 2×2 comparisons, membrane potential and Ca2+ functional parameters during AP cycle were significantly correlated with each other, and each was corelated with the mean APFI and APFIV. In unbiased, principle component analyses of all mean and SD's, the first 3 principal components accounted for 86.8% of the total variance. Distributions of coupled clock regulatory parameter mean values and their beat to beat variabilities over the entire range of APFI obeyed similar power laws. We conclude that both APFIV and mean APFI, within and across “steady states”, emerge from coherent beat to beat variability of M- and Ca2+-clock regulatory functions that inform on self-similar organization of availability of molecules that underlie these measured clock functions to become activated in response to voltage or Ca2+ cues during an AP cycle.