Phosphorylation of Ca v 1.2 on S1928 uncouples the L‐type Ca 2+ channel from the β 2 adrenergic receptor

Autor: Hai Qian, Tommaso Patriarchi, Geoffrey G. Murphy, William A. Catterall, Franz Hofmann, Olivia R. Buonarati, Chao Ye Chen, Erik A. Hammes, Ruth E. Westenbroek, Jennifer L. Price, Yang Kevin Xiang, Zulfiquar A. Malik, Dhrubajyoti Chowdhury, Manuel F. Navedo, Johannes W. Hell, Valentina Di Biase
Rok vydání: 2016
Předmět:
0301 basic medicine
medicine.medical_specialty
Calcium Channels
L-Type
Adrenergic receptor
1.1 Normal biological development and functioning
L-type calcium channels
beta-2
Stimulation
Biology
Medical and Health Sciences
General Biochemistry
Genetics and Molecular Biology
L‐type calcium channels
Mice
03 medical and health sciences
Downregulation and upregulation
Underpinning research
Postsynaptic potential
Information and Computing Sciences
Internal medicine
Receptors
medicine
Animals
Phosphorylation
Protein kinase A
Receptor
Molecular Biology
Protein Processing
General Immunology and Microbiology
General Neuroscience
Post-Translational
Neurosciences
Long-term potentiation
Articles
Biological Sciences
L-Type
Cell biology
030104 developmental biology
Endocrinology
Adrenergic
glutamate receptors
protein kinase A
Receptors
Adrenergic
beta-2
Calcium Channels
adrenergic receptors
Protein Processing
Post-Translational
Developmental Biology
Zdroj: The EMBO journal, vol 35, iss 12
ISSN: 1460-2075
0261-4189
DOI: 10.15252/embj.201593409
Popis: Agonist‐triggered downregulation of β‐adrenergic receptors (ARs) constitutes vital negative feedback to prevent cellular overexcitation. Here, we report a novel downregulation of β2 AR signaling highly specific for Cav1.2. We find that β2‐AR binding to Cav1.2 residues 1923–1942 is required for β‐adrenergic regulation of Cav1.2. Despite the prominence of PKA‐mediated phosphorylation of Cav1.2 S1928 within the newly identified β2 AR binding site, its physiological function has so far escaped identification. We show that phosphorylation of S1928 displaces the β2 AR from Cav1.2 upon β‐adrenergic stimulation rendering Cav1.2 refractory for several minutes from further β‐adrenergic stimulation. This effect is lost in S1928A knock‐in mice. Although AMPARs are clustered at postsynaptic sites like Cav1.2, β2 AR association with and regulation of AMPARs do not show such dissociation. Accordingly, displacement of the β2 AR from Cav1.2 is a uniquely specific desensitization mechanism of Cav1.2 regulation by highly localized β2 AR/cAMP/PKA/S1928 signaling. The physiological implications of this mechanism are underscored by our finding that LTP induced by prolonged theta tetanus (PTT‐LTP) depends on Cav1.2 and its regulation by channel‐associated β2 AR.
Databáze: OpenAIRE
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