Phosphorylation of Cav1.2 on S1928 uncouples the L-type Ca2+ channel from the β2 adrenergic receptor.
Agonist-triggered downregulation of β-adrenergic receptors (ARs) constitutes vital negative feedback to prevent cellular overexcitation. Here, we report a novel downregulation of β2AR 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 β2AR binding site, its physiological function has so far escaped identification. We show that phosphorylation of S1928 displaces the β2AR 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, β2AR association with and regulation of AMPARs do not show such dissociation. Accordingly, displacement of the β2AR from Cav1.2 is a uniquely specific desensitization mechanism of Cav1.2 regulation by highly localized β2AR/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 β2AR.
Department of Pharmacology, University of California, Davis, CA, USA.
Tommaso
T
Patriarchi
Department of Pharmacology, University of Iowa, Iowa City, IA, USA.
Hai
H
Qian
Institute for Biophysics, Medical University of Graz, Graz, Austria.
Valentina
V
Di Biase
Department of Pharmacology, University of California, Davis, CA, USA Department of Pharmacology, University of Iowa, Iowa City, IA, USA.
Zulfiquar A
ZA
Malik
Department of Pharmacology, University of California, Davis, CA, USA.
Dhrubajyoti
D
Chowdhury
Department of Pharmacology, University of California, Davis, CA, USA.
Jennifer L
JL
Price
Department of Pharmacology, University of California, Davis, CA, USA.
Erik A
EA
Hammes
Department of Pharmacology, University of California, Davis, CA, USA.
Olivia R
OR
Buonarati
Department of Pharmacology, University of Washington, Seattle, WA, USA.
Ruth E
RE
Westenbroek
Department of Pharmacology, University of Washington, Seattle, WA, USA.
William A
WA
Catterall
Department of Pharmacology and Toxicology, Technical University of Munich, Munich, Germany.
Franz
F
Hofmann
Department of Pharmacology, University of California, Davis, CA, USA.
Yang K
YK
Xiang
Department of Molecular & Integrative Physiology, Molecular & Behavioral Neuroscience Institute University of Michigan, Ann Arbor, MI, USA.
Geoffrey G
GG
Murphy
Department of Pharmacology, University of California, Davis, CA, USA.
Chao-Ye
CY
Chen
Department of Pharmacology, University of California, Davis, CA, USA.
Manuel F
MF
Navedo
Department of Pharmacology, University of California, Davis, CA, USA Department of Pharmacology, University of Iowa, Iowa City, IA, USA jwhell@ucdavis.edu.
Johannes W
0000-0001-7960-7531
JW
Hell
D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*
C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D018343:Receptors, Adrenergic, beta-2
L‐type calcium channels; adrenergic receptors; glutamate receptors; protein kinase A