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

Abstract

Inward rectifying (KIR) 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 KIR channels were uniquely modulated by membrane lipids and hemodynamic stimuli. A KIR current was isolated in smooth muscle and endothelial cells of rat cerebral arteries and molecular analyses confirmed KIR2.1/KIR2.2 mRNA and protein expression. Electrophysiology next revealed that endothelial KIR was sensitive to phosphatidylinositol 4,5- bisphosphate (PIP2), with depletion impairing flow-induced activation of the channel. In contrast, smooth muscle KIR was sensitive to membrane cholesterol, with sequestration blocking pressures ability to inhibit this channel. Membrane lipids helped confer KIR mechanosensitivity to intact arteries; virtual models then reconceptualised KIR as a dynamic regulator of basal tone development. We conclude that specific membrane lipid-KIR interactions enable unique channel populations to sense hemodynamic stimuli and set brain perfusion.