Membrane Lipid-K2.x Channel Interactions Enable Hemodynamic Sensing in Cerebral Arteries.

Objective- Inward rectifying K (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. This study defined whether distinct pools of cerebral arterial K channels were uniquely modulated by membrane lipids and hemodynamic stimuli. Approach and Results- A Ba-sensitive K current was isolated in smooth muscle and endothelial cells of rat cerebral arteries; molecular analyses subsequently confirmed K2.1/K2.2 mRNA and protein expression in both cells. Patch-clamp electrophysiology next demonstrated that each population of K channels was sensitive to key membrane lipids and hemodynamic stimuli. In this regard, endothelial K was sensitive to phosphatidylinositol 4,5-bisphosphate content, with depletion impairing the ability of laminar shear stress to activate this channel pool. In contrast, smooth muscle K was sensitive to membrane cholesterol content, with sequestration blocking the ability of pressure to inhibit channel activity. The idea that membrane lipids help confer shear stress and pressure sensitivity of K channels was confirmed in intact arteries using myography. Virtual models integrating structural/electrical observations reconceptualized K as a dynamic regulator of membrane potential working in concert with other currents to set basal tone across a range of shear stresses and intravascular pressures. Conclusions- The data show for the first time that specific membrane lipid-K interactions enable unique channel populations to sense hemodynamic stimuli and drive vasomotor responses to set basal perfusion in the cerebral circulation.