Sympathetic stimulation of heart rate in the SA node. (A) Simulated voltage (top) and currents (bottom) in an SA node cell during rest (solid lines) and sympathetic stimulation (dashed lines). Sympathetic stimulation was simulated by shifting the voltage dependence of HCN channels to more depolarized potentials while all other parameters were the same (model from Elinder et al., 2006, based on a rabbit SA node model from Zhang et al., 2000). Only the currents through HCN (I_f), T-type and L-type Ca (combined to one I_Ca current for display), Herg channels (I_Kr), and Na⁺/Ca²⁺ exchangers (I_NaCa) are shown. In this model, sympathetic stimulation increases the inward HCN currents, thereby increasing the rate of depolarization and the action potential firing (dashed lines). Notice that the net (total) current (I_tot) is very small during diastole (a few pA), and that it is the sum of many different currents of larger size with opposite polarity. The small net current during diastole is one of the reasons for the difficulty in clearly assigning one channel as generating the currents that drive the pacemaking in the SA node. (B) SA node cell with some of the possible pathways for the effect of sympathetic stimulation on pacemaking (Lakatta et al., 2010). β-adrenergic–stimulated G protein–coupled receptors (β-Ad-R) activate adenylyl cyclases (red AC) that produce cAMP. Rising concentrations of cAMP activate PKA that directly modulates HCN channels and other protein targets. PKA phosphorylates ryanodine receptors (RyR) and SERCA Ca²⁺ pumps that then alters the Ca²⁺ cycling from the sarcoplasmic reticulum (SR) and alters cytosolic Ca²⁺ oscillations. Increased Ca²⁺ levels also activate basal adenylyl cyclase (yellow AC) through calmodulin (CaM). Increased cytosolic Ca²⁺ also increases the inward currents through Na⁺/Ca²⁺ exchangers (I_NaCa). Protein phosphatases (PP) dephosphorylate HCN channels, as well as inhibit phosphodiesterases (PDE) that otherwise would break down cAMP.