Figure 4.

The origin of the heartbeat: coupled-clock pacemaker system in the sinoatrial cells. The pacemaker activity of the SA node originates from the membrane and calcium clock mechanisms. The former is composed of the sarcolemmal channel proteins, and the latter results from sarcoplasmic reticulum and sarcoplasmic Ca²⁺ turnover. At end of the SA action potential the hyperpolarization-activated I_f depolarizes the membrane to a level where Ca²⁺ channels open. In addition, during late diastole, spontaneous SR Ca²⁺ releases further depolarize the membrane by activating I_NCX. Ca²⁺ can bind to calmodulin and activate adenylyl cyclase (AC). High constitutive activation of AC leading to high basal level of cAMP (which is needed for protein kinase A-dependent phosphorylation) in SA node cells has been suggested to contribute to the Ca²⁺ overload state. PKA-dependent phosphorylation of phospholamban, I_Ca,L, and RyR promotes spontaneous Ca²⁺ release. Blue shows the membrane clock and red shows the calcium clock mechanism. Solid arrows show the Ca²⁺-induced Ca²⁺ release process and spontaneous Ca²⁺ release events via RyR; dashed arrows show the phosphorylation targets of the cAMP–PKA pathway. I_Ca,L, L-type Ca²⁺ current; I_Ca,T, T-type Ca²⁺ current; I_NCX, Na⁺-Ca²⁺ exchange; I_f, funny current; I_to, transient outward K⁺ current; I_Ks, slow component of delayed rectifier K⁺ current; I_Kr, rapid component of delayed rectifier K⁺ current; I_K1, inward rectifier K⁺ current; I_Kur, ultra rapid component of delayed rectifier K⁺ current; RyR, ryanodine receptor; SERCA, sarcoplasmic reticulum Ca²⁺-ATPase; PLN, phospholamban; CaM, calmodulin; AC, adenylyl cyclase; PKA, protein kinase A; CICR, Ca²⁺-induced Ca²⁺ release; SA, sinoatrial.