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Proteolytic cleavage and PKA phosphorylation of ?1C subunit are not required for adrenergic regulation of CaV1.2 in the heart.

ABSTRACT: Calcium influx through the voltage-dependent L-type calcium channel (CaV1.2) rapidly increases in the heart during "fight or flight" through activation of the ?-adrenergic and protein kinase A (PKA) signaling pathway. The precise molecular mechanisms of ?-adrenergic activation of cardiac CaV1.2, however, are incompletely known, but are presumed to require phosphorylation of residues in ?1C and C-terminal proteolytic cleavage of the ?1C subunit. We generated transgenic mice expressing an ?1C with alanine substitutions of all conserved serine or threonine, which is predicted to be a potential PKA phosphorylation site by at least one prediction tool, while sparing the residues previously shown to be phosphorylated but shown individually not to be required for ?-adrenergic regulation of CaV1.2 current (17-mutant). A second line included these 17 putative sites plus the five previously identified phosphoregulatory sites (22-mutant), thus allowing us to query whether regulation requires their contribution in combination. We determined that acute ?-adrenergic regulation does not require any combination of potential PKA phosphorylation sites conserved in human, guinea pig, rabbit, rat, and mouse ?1C subunits. We separately generated transgenic mice with inducible expression of proteolytic-resistant ?1C Prevention of C-terminal cleavage did not alter ?-adrenergic stimulation of CaV1.2 in the heart. These studies definitively rule out a role for all conserved consensus PKA phosphorylation sites in ?1C in ?-adrenergic stimulation of CaV1.2, and show that phosphoregulatory sites on ?1C are not redundant and do not each fractionally contribute to the net stimulatory effect of ?-adrenergic stimulation. Further, proteolytic cleavage of ?1C is not required for ?-adrenergic stimulation of CaV1.2.

SUBMITTER: Katchman A 

PROVIDER: S-EPMC5576811 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Proteolytic cleavage and PKA phosphorylation of α<sub>1C</sub> subunit are not required for adrenergic regulation of Ca<sub>V</sub>1.2 in the heart.

Katchman Alexander A   Yang Lin L   Zakharov Sergey I SI   Kushner Jared J   Abrams Jeffrey J   Chen Bi-Xing BX   Liu Guoxia G   Pitt Geoffrey S GS   Colecraft Henry M HM   Marx Steven O SO  

Proceedings of the National Academy of Sciences of the United States of America 20170807 34

Calcium influx through the voltage-dependent L-type calcium channel (Ca<sub>V</sub>1.2) rapidly increases in the heart during "fight or flight" through activation of the β-adrenergic and protein kinase A (PKA) signaling pathway. The precise molecular mechanisms of β-adrenergic activation of cardiac Ca<sub>V</sub>1.2, however, are incompletely known, but are presumed to require phosphorylation of residues in α<sub>1C</sub> and C-terminal proteolytic cleavage of the α<sub>1C</sub> subunit. We gene  ...[more]

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