FIGURE 6.

Effects of autonomic nervous system activity on the coupled clock system of pacemaking

A: schematic illustration of the effects of adrenergic stimulation on the coupled clock system of pacemaking. In vivo, epinephrine produced from the adrenal glands and norepinephrine from sympathetic nerve terminals binds to β-adrenoceptors, also known as G-protein-coupled receptors. This leads to the Gs subunit activating G-protien-coupled receptor-activated, Ca²⁺-inhibited adenylate cylases (ACs), which produce cAMP from ATP in additional quantities to that being made by constitutively active, Ca²⁺-stimulated ACs. This additional cAMP further activates PKA (and I_f) to lead to an increase in levels of phosphorylation of critical mediators of automaticity belonging to both the membrane and Ca²⁺ clocks. This in turn leads to the overall levels of intracellular Ca²⁺ being higher, with subsequently higher levels of activation of calmodulin and thence CAMKII, with more phosphorylation. The ultimate effect is more rapid cycling of greater amounts of Ca²⁺, and hence an increase in the ticking speed of the coupled clock system. B: schematic illustration of the effects of muscarinic stimulation on the coupled clock system of pacemaking. Acetylcholine (ACh) produced from parasympathetic nerve terminals binds to muscarinic receptors (MR) on SANC (MR also being a form of G-protein-coupled receptors), leading to two predominant effects. The first of these is the direct interaction between the gβγ subunit and I_K,ACh, which leads to an outward, repolarizing K⁺ current. The second effect is that the giα subunit interacts directly with G-protein-coupled receptor-coupled ACs to inhibit these enzymes, causing a decrease in the amount of cAMP produced, with less activation of PKA (and I_f). Less activation of PKA means that levels of phosphorylation fall, with levels of intracellular Ca²⁺ falling too. Less intracellular Ca²⁺ means less activation of CAMKII, so even less phosphorylation. The combined effects of I_K,ACh activation and AC inhibition means a slower rate of ticking of the coupled clock system.