Phosphorylation of Cav1.2 on S1928 uncouples the L‐type Ca2+ channel from the β2 adrenergic receptor

Abstract Agonist‐triggered downregulation of β‐adrenergic receptors (ARs) 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 AMPARs are clustered at postsynaptic sites like Ca v 1.2, β 2 AR association with and regulation of AMPARs 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.