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Phosphorylation of Ca v 1.2 on S1928 uncouples the L‐type Ca 2+ channel from the β 2 adrenergic receptor
Author(s) -
Patriarchi Tommaso,
Qian Hai,
Di Biase Valentina,
Malik Zulfiquar A,
Chowdhury Dhrubajyoti,
Price Jennifer L,
Hammes Erik A,
Buonarati Olivia R,
Westenbroek Ruth E,
Catterall William A,
Hofmann Franz,
Xiang Yang K,
Murphy Geoffrey G,
Chen ChaoYe,
Navedo Manuel F,
Hell Johannes W
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201593409
Subject(s) - biology , phosphorylation , biophysics , microbiology and biotechnology
Agonist‐triggered downregulation of β‐adrenergic receptors ( AR s) constitutes vital negative feedback to prevent cellular overexcitation. Here, we report a novel downregulation of β 2 AR signaling highly specific for Ca v 1.2. We find that β 2 ‐ AR binding to Ca v 1.2 residues 1923–1942 is required for β‐adrenergic regulation of Ca v 1.2. Despite the prominence of PKA ‐mediated phosphorylation of Ca v 1.2 S1928 within the newly identified β 2 AR binding site, its physiological function has so far escaped identification. We show that phosphorylation of S1928 displaces the β 2 AR from Ca v 1.2 upon β‐adrenergic stimulation rendering Ca v 1.2 refractory for several minutes from further β‐adrenergic stimulation. This effect is lost in S1928A knock‐in mice. Although AMPAR s are clustered at postsynaptic sites like Ca v 1.2, β 2 AR association with and regulation of AMPAR s do not show such dissociation. Accordingly, displacement of the β 2 AR from Ca v 1.2 is a uniquely specific desensitization mechanism of Ca v 1.2 regulation by highly localized β 2 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 Ca v 1.2 and its regulation by channel‐associated β 2 AR .