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- _4 value "FIG. 24. Summary of the signaling pathways involved in the muscarinic regulation of pacemaker activity. In the SAN and AVN, ACh and Ado share the same pathways for signal transduction. ACh binds to the muscarinic M2 receptor, which is coupled to a \"direct\" G protein-dependent pathway activating Kir3.1/Kir3.4 (GIRK1/GIRK4) channel complexes. Beside this direct pathway, two other \"indirect\" channel regulation pathways lead to downregulation of intracellular cAMP. In the first cascade of events, the {alpha}Gi protein subunit inhibits AC activity, thereby reducing the synthesis of cAMP. Inhibition of AC synthesis is viewed as the predominant pathway by which ACh regulates the voltage dependence of f-channels (HCN). The second muscarinic pathway is initiated by the stimulation of the NOS activity and production of NO. NOS activates the enzyme guanylate cyclase (GC), which converts GTP in cGMP. Elevation of cGMP concentration stimulates PDE II-dependent hydrolysis of cAMP, thereby reducing PKA activity. This NOS-dependent pathway for regulation of PKA activity has been proposed to be the major pathway for the muscarinic regulation of ICa,L during pacemaking. In the figure, negative NOS-dependent regulation of Cav1.3-mediated ICa,L and Ist is suggested. It is not known if the SAN IKr can also be negatively regulated by the NOS-dependent pathway." provenance.
- _4 wasQuotedFrom 18626064 provenance.