β-Adrenergic Regulation of the L-Type Ca²⁺ Channel Ca_V1.2 by PKA Rekindles Excitement

Johannes W. Hell^*

Department of Pharmacology, University of California, Davis, CA 95615, USA.

Abstract: 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_V1.2, 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_V1.2 has been considered the holy grail for the field of channel regulation. New evidence from the quest to solve the mystery of Ca_V1.2 regulation has revealed that reproducible reconstitution of this regulation in heterologous cells requires a perfect balance of the ratio of Ca_V1.2 to A-kinase anchor proteins (AKAPs). Proteolytic processing of the cytosolic C terminus of the central, pore-forming ₁1.2 subunit of Ca_V1.2 contributed to its regulation by PKA, and Ser¹⁷⁰⁰ in the C terminus of the ₁1.2 subunit emerged as the relevant PKA phosphorylation site.

* Corresponding author. E-mail, jwhell{at}ucdavis.edu

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