Beta-adrenergic regulation of the L-type Ca2+ channel Ca(V)1.2 by PKA rekindles excitement.
When we are frightened, our hearts beat more rapidly and forcefully so we can fight more intensely or run away faster. This fight-or-flight response is triggered by the release of norepinephrine from neurons of the sympathetic nervous system. Norepinephrine activates the classic β-adrenergic receptor-heterotrimeric G(s) protein-adenylyl cyclase-adenosine 3',5'-monophosphate-protein kinase A (PKA) signaling cascade. One of the main PKA targets implicated in this response is the L-type Ca2+ channel Ca(V)1.2, which mediates Ca2+ influx into cardiomyocytes. Because of its central function in regulating heartbeat, and because the underlying molecular mechanism has remained elusive, understanding the regulation of Ca(V)1.2 has been considered the holy grail for the field of channel regulation. New evidence from the quest to solve the mystery of Ca(V)1.2 regulation has revealed that reproducible reconstitution of this regulation in heterologous cells requires a perfect balance of the ratio of Ca(V)1.2 to A-kinase anchor proteins (AKAPs). Proteolytic processing of the cytosolic C terminus of the central, pore-forming α₁1.2 subunit of Ca(V)1.2 contributed to its regulation by PKA, and Ser(1700) in the C terminus of the α₁1.2 subunit emerged as the relevant PKA phosphorylation site.
Hell
Johannes W
JW
Department of Pharmacology, University of California, Davis, CA 95615, USA. jwhell@ucdavis.edu
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D017136:Ion Transport; D051379:Mice; D010766:Phosphorylation
D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium