Postsynaptic density‐95 (PSD95) mediates vasodilator signaling between β1 adrenergic receptor and Shaker ‐type K + (K V 1) channel in rat cerebral arteries

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 K V 1 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 (EC 50 ~ 200 nM) was blocked by a selective β1AR blocker, CGP20712 , as well as K V 1 channel blockers, correolide and 5‐(4‐phenylalkoxypsoralen). Next, we designed a membrane‐permeable peptide that mimics the carboxyl‐terminus of K V 1 channels (K V 1‐C) and competes for the binding to PSD95. Application of this K V 1‐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 K V 1‐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‐K V 1 vasodilator signaling pathway in cerebral arteries. Funded by NIH R01 HL097107 (SWR).