The sinoatrial node is the primary pacemaker of the heart. Recent data have demonstrated that sinoatrial node cells (SANC) generate rhythmic local subsarcolemmal Ca2+ releases (LCRs) from sarcoplasmic reticulum (SR) ryanodine receptors (RyR). LCRs occur spontaneously and do not require membrane depolarization; they occur during the second half of the diastolic depolarization (DD) and activate an inward Na+-Ca2+ (NCX) exchange current, accelerating rate of the late DD, and thus exerting potent regulation of the spontaneous SANC beating rate, i.e., normal automaticity. When LCRs are inhibited by ryanodine the spontaneous beating rate is markedly decreased. Our prior studies have also demonstrated Ca2+-activated adenylyl cyclase (AC) activity, and high basal cAMP-mediated PKA-dependent protein phosphorylation in SANC. A high basal phosphodiesterase (PDE) activity provide a potent negative regulation of cAMP-PKA dependent phosphorylation and thus of LCR parameters. Suppression of PDE activity: markedly decreases the LCR period; increases LCR number and size, leading to earlier and amplified local Ca2+ release and NCX current, an earlier AP upstroke and thus to an increase in the spontaneous beating rate. Beta-AR stimulation (beta-AR) increases the spontaneous beating rate above the basal level by utilizing the same mechanism as PDE inhibition, i.e., through modification of LCR characteristics: decrease in the LCR period and increase in LCR number and size. When RyR Ca2+ release is disabled by ryanodine neither PDE inhibition, nor beta-AR stimulation has a substantial chronotropic effect.
