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.
This work identifies Cav1.2 S1928 phosphorylation as negative feedback mechanism for Ca2+ channel regulation by β2AR/cAMP/PKA signaling in neurons. This desensitization is highly specific as nearby β2AR/PKA/AMPA receptor signaling is not attenuated.
β2AR–Cav1.2 binding at S1928 is required for channel regulation in neurons
Phosphorylation of S1928 specifically displaces the β2AR from Cav1.2
β2AR displacement prevents subsequent Cav1.2 phosphorylation and regulation
β2AR–Cav1.2 interaction is necessary for the induction of PTT‐LTP
- Received October 31, 2015.
- Revision received March 23, 2016.
- Accepted March 24, 2016.
- © 2016 The Authors
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