Postsynaptic Density-95 (PSD95) Scaffolding of Shaker-type K+ Channelsin Smooth Muscle Cells Regulates the Diameter of Cerebral Arteries

Postsynaptic density-95 (PSD95) is a 95 kDa scaffolding molecule in the brain that clusters postsynaptic proteins including ion channels, receptors, enzymes and other signaling partners required for normal cognition. Voltage-gated, Shaker-type, K+ (KV1) channels are key binding partners of PSD95 scaffolds in postsynaptic neurons. KV1 channels composed of α1.2 and α1.5 pore-forming subunits also are expressed in the vascular smooth muscle cells (cVSMCs) of the cerebral circulation, although the identity of their molecular scaffolds is unknown. However, since α1.2 contains a binding motif for PSD95, we explored the possibility that cVSMCs express PSD95 as a scaffold to promote KV1 channel expression and enhance vasodilation of cerebral arteries. Cerebral arteries from Sprague-Dawley rats were isolated for analysis of PSD95 and KV1 channel proteins. PSD95 was detected in cVSMCs and it co-immunoprecipitated and co-localized with the pore-forming α1.2 subunit of the KV1 channel. Antisense-mediated knockdown of PSD95 profoundly reduced KV1 channel expression and patch-clamped cVSMCs exhibited a loss of KV1 current. Loss of PSD95 also depolarized cVSMCs in pressurized cerebral arteries and induced a strong constriction associated with a loss of functional KV1 channels. Our findings provide initial evidence that PSD95 is expressed in cVSMCs, and KV1 channels are one of its important binding partners. PSD95 appears to function as a critical \"dilator\" scaffold in cerebral arteries by increasing the number of functional KV1 channels at the plasma membrane.