Muscarinic cholinergic signaling in cardiac myocytes: Dynamic targeting ofM2AChR to sarcolemmal caveolae and eNOS activation

The isoform of nitric oxide synthase (eNOS or NOS3) originally described in endothelial cells is also expressed in a number of other cell types, inclu ding cardiac myocytes. eNOS is activated in both atrial and ventricular myo cytes, including specialized pacemaker cells, by M2AChR agonists, among oth er stimuli. In cardiac myocytes, as in endothelial cells, eNOS is targeted to sarcolemmal caveolae, due to both co-translational myristoylation and la ter palmitoylation, and by the presence of a caveolin binding domain in eNO S which interacts with the caveolin scaffolding domain. In the absence of l igand, the M2AChR is not associated with caveolar microdomains, but transla tes into caveolae upon agonist (but not antagonist) binding. Finally, the r ole of M2AChR-induced eNOS activation in regulating ICa-L via activation of guanylyl cyclase has been confirmed in ventricular myocytes of mice that l ack functional eNOS (i.e., eNOS(null)).