Vascular Inward Rectifier K+ Channels as External K+ Sensors in the Control of Cerebral Blood Flow

For decades it has been known that external K+ ions are rapid and potent vasodilators that increase CBF. Recent studies have implicated the local release of K+ from astrocytic endfeetwhich encase the entirety of the parenchymal vasculaturein the dynamic regulation of local CBF during NVC. It has been proposed that the activation of K-IR channels in the vascular wall by external K+ is a central component of these hyperemic responses; however, a number of significant gaps in our knowledge remain. Here, we explore the concept that vascular K-IR channels are the major extracellular K+ sensors in the control of CBF. We propose that K+ is an ideal mediator of NVC, and discuss K-IR channels as effectors that produce rapid hyperpolarization and robust vasodilation of cerebral arterioles. We provide evidence that K-IR channels, of the K(IR)2 subtype in particular, are present in both the endothelial and SM cells of parenchymal arterioles and propose that this dual positioning of K(IR)2 channels increases the robustness of the vasodilation to external K+, enables the endothelium to be actively engaged in NVC, and permits electrical signaling through the endothelial syncytium to promote upstream vasodilation to modulate CBF.