Molecular determinants of beta-adrenergic signaling to voltage-gated K⁺ channels in the cerebral circulation

Voltage-gated K⁺ (K_v ) channels are major determinants of membrane potential in vascular smooth muscle cells (VSMCs) and regulate the diameter of small cerebral arteries and arterioles. However, the intracellular structures that govern the expression and function of vascular K_v channels are poorly understood. Scaffolding proteins including postsynaptic density 95 (PSD95) recently were identified in rat cerebral VSMCs. Primarily characterized in neurons, the PSD95 scaffold has more than 50 known binding partners, and it can mediate macromolecular signaling between cell-surface receptors and ion channels. In cerebral arteries, Shaker-type K_v 1 channels appear to associate with the PSD95 molecular scaffold, and PSD95 is required for the normal expression and vasodilator influence of members of this K⁺ channel gene family. Furthermore, recent findings suggest that the β1-subtype adrenergic receptor is expressed in cerebral VSMCs and forms a functional vasodilator complex with K_v 1 channels on the PSD95 scaffold. Activation of β1-subtype adrenergic receptors in VSMCs enables protein kinase A-dependent phosphorylation and opening of K_v 1 channels in the PSD95 complex; the subsequent K⁺ efflux mediates membrane hyperpolarization and vasodilation of small cerebral arteries. Early evidence from other studies suggests that other families of K_v channels and scaffolding proteins are expressed in VSMCs. Future investigations into these macromolecular complexes that modulate the expression and function of K_v channels may reveal unknown signaling cascades that regulate VSMC excitability and provide novel targets for ion channel-based medications to optimize vascular tone.