Phosphorylation of Ser1928 mediates the enhanced activity of the L-type Ca2+ channel Cav1.2 by the β2-adrenergic receptor in neurons

Hai Qian; Tommaso Patriarchi; Jennifer L Price; Lucas Matt; Boram Lee; Madeline Nieves-Cintrón; Olivia R Buonarati; Dhrubajyoti Chowdhury; Evanthia Nanou; Matthew A Nystoriak; William A Catterall; Montatip Poomvanicha; Franz Hofmann; Manuel F Navedo; Johannes W Hell

doi:10.1126/scisignal.aaf9659

Phosphorylation of Ser1928 mediates the enhanced activity of the L-type Ca2+ channel Cav1.2 by the β2-adrenergic receptor in neurons

Sci Signal. 2017 Jan 24;10(463):eaaf9659. doi: 10.1126/scisignal.aaf9659.

Authors

Hai Qian¹, Tommaso Patriarchi², Jennifer L Price², Lucas Matt², Boram Lee², Madeline Nieves-Cintrón², Olivia R Buonarati², Dhrubajyoti Chowdhury², Evanthia Nanou³, Matthew A Nystoriak², William A Catterall³, Montatip Poomvanicha⁴, Franz Hofmann⁴, Manuel F Navedo⁵, Johannes W Hell^{6

2}

Affiliations

¹ Department of Pharmacology, University of Iowa, Iowa City, IA 52242-1109, USA.
² Department of Pharmacology, University of California, Davis, CA 95616-8636, USA.
³ Department of Pharmacology, University of Washington, Seattle, WA 98195-7280, USA.
⁴ Department of Pharmacology and Toxicology, Technical University of Munich, D-80802 Munich, Germany.
⁵ Department of Pharmacology, University of California, Davis, CA 95616-8636, USA. mfnavedo@ucdavis.edu jwhell@ucdavis.edu.
⁶ Department of Pharmacology, University of Iowa, Iowa City, IA 52242-1109, USA. mfnavedo@ucdavis.edu jwhell@ucdavis.edu.

Abstract

The L-type Ca²⁺ channel Ca_v1.2 controls multiple functions throughout the body including heart rate and neuronal excitability. It is a key mediator of fight-or-flight stress responses triggered by a signaling pathway involving β-adrenergic receptors (βARs), cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA). PKA readily phosphorylates Ser¹⁹²⁸ in Ca_v1.2 in vitro and in vivo, including in rodents and humans. However, S1928A knock-in (KI) mice have normal PKA-mediated L-type channel regulation in the heart, indicating that Ser¹⁹²⁸ is not required for regulation of cardiac Ca_v1.2 by PKA in this tissue. We report that augmentation of L-type currents by PKA in neurons was absent in S1928A KI mice. Furthermore, S1928A KI mice failed to induce long-term potentiation in response to prolonged theta-tetanus (PTT-LTP), a form of synaptic plasticity that requires Ca_v1.2 and enhancement of its activity by the β₂-adrenergic receptor (β₂AR)-cAMP-PKA cascade. Thus, there is an unexpected dichotomy in the control of Ca_v1.2 by PKA in cardiomyocytes and hippocampal neurons.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adrenergic beta-Agonists / pharmacology
Adrenergic beta-Antagonists / pharmacology
Animals
Calcium Channels, L-Type / genetics
Calcium Channels, L-Type / metabolism*
Calcium Channels, L-Type / physiology
Cells, Cultured
Cyclic AMP-Dependent Protein Kinases / metabolism
Female
Imidazoles / pharmacology
Isoproterenol / pharmacology
Long-Term Potentiation / drug effects
Male
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Transgenic
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / metabolism
Myocytes, Cardiac / physiology
Neuronal Plasticity / drug effects
Neurons / drug effects
Neurons / metabolism*
Neurons / physiology
Phosphorylation / drug effects
Propanolamines / pharmacology
Rats, Sprague-Dawley
Receptors, Adrenergic, beta-2 / genetics
Receptors, Adrenergic, beta-2 / metabolism*
Serine / genetics
Serine / metabolism*
Signal Transduction / drug effects

Substances

Adrenergic beta-Agonists
Adrenergic beta-Antagonists
Calcium Channels, L-Type
Imidazoles
L-type calcium channel alpha(1C)
Propanolamines
Receptors, Adrenergic, beta-2
Serine
ICI 118551
CGP 20712A
Cyclic AMP-Dependent Protein Kinases
Isoproterenol

Abstract

Publication types

MeSH terms

Substances

Grants and funding