Membrane Lipid-KIR2.x Channel Interactions Enable Hemodynamic Sensing in Cerebral Arteries

Inward rectifying (K IR ) K + channels are present in cerebral arterial smooth muscle and endothelial cells, a tandem arrangement suggestive of a dynamic yet undiscovered role for this channel. We explored whether vascular K IR channels were uniquely modulated by membrane lipids and hemodynamic stimuli. A K IR current was isolated in smooth muscle and endothelial cells of rat cerebral arteries and molecular analyses confirmed K IR 2.1/K IR 2.2 mRNA and protein expression. Electrophysiology next revealed that endothelial K IR was sensitive to phosphatidylinositol 4,5- bisphosphate (PIP 2 ), with depletion impairing flow-induced activation of the channel. In contrast, smooth muscle K IR was sensitive to membrane cholesterol, with sequestration blocking pressure’s ability to inhibit this channel. Membrane lipids helped confer K IR mechanosensitivity to intact arteries; virtual models then reconceptualised K IR as a dynamic regulator of basal tone development. We conclude that specific membrane lipid-K IR interactions enable unique channel populations to sense hemodynamic stimuli and set brain perfusion.