Postsynaptic density‐95 (PSD95) mediates vasodilator signaling between β1 adrenergic receptor and Shaker‐type K+ (KV1) channel in rat cerebral arteries

Abstract

We recently reported the expression of scaffolding protein postsynaptic density‐95 (PSD95) in the rat cerebral vascular smooth muscle cells (cVSMC). PSD95 binds with the KV1 channels at the plasma membrane of cVSMC to mediate vasodilation. In this study, we explored whether the beta1 adrenergic receptor (β1AR) expressed in several vascular beds forms a signaling complex with PSD95 in cVSMC. By immunohistochemistry, we observed that β1AR is expressed in rat cVSMC and co‐localizes with PSD95. In pressurized cerebral arteries, isoproterenol‐induced vasodilation (EC50 ~ 200 nM) was blocked by a selective β1AR blocker, CGP20712, as well as KV1 channel blockers, correolide and 5‐(4‐phenylalkoxypsoralen). Next, we designed a membrane‐permeable peptide that mimics the carboxyl‐terminus of KV1 channels (KV1‐C) and competes for the binding to PSD95. Application of this KV1‐C peptide (10 μM) to pressurized arteries caused vasoconstriction and significantly blunted the vasodilation induced by isoproterenol. Interestingly, application of protein kinase inhibitor peptides (PKI, 1 μM) against protein kinase A elicited almost identical responses to those observed with KV1‐C peptide. Taken together, our study provides initial evidence that β1AR may be another key binding partner of PSD95 in cVSMC, and that PSD95 mediates β1AR‐KV1 vasodilator signaling pathway in cerebral arteries. Funded by NIH R01 HL097107 (SWR).