Novel Perspectives on Cardiac Pacemaker Regulation: Role of the Coupled Function of Sarcolemmal and Intracellular Proteins

Recent experimental and theoretical studies demonstrate that the sinoatrial node cells (SANCs), the primary pacemaker cells of heart, operate as a complex system of functionally coupled sarcolemmal and intracellular proteins. The proteins of this system dynamically (beat-to-beat) interact throughout the entire pacemaker cycle via membrane voltage and local subsarcolemmal Ca2+ changes. Furthermore, functions of the sarcolemmal (SL) electrogenic proteins and sarcoplasmic reticulum (SR) Ca2+ cycling proteins are coupled and regulated enzymatically via Ca2+-, PKA-, and CaMKII-dependent protein phosphorylation. The system is not only robust (i.e., fail-safe within wide parameter range), but simultaneously flexible, because the autonomic neural modulation of the beating rate, via G protein-coupled receptor (GPCR) signaling, acts upon the very same regulatory factors (i.e., the coupling factors, Ca2+, PKA, and CaMKII) that ensure and regulate robust system function in the basal state. This chapter summarizes the experimental and theoretical evidences for this novel pacemaker concept.