Objective—
Inward rectifying K
+
(K
IR
) 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
IR
channels were uniquely modulated by membrane lipids and hemodynamic stimuli.
Approach and Results—
A Ba
2+
-sensitive K
IR
current was isolated in smooth muscle and endothelial cells of rat cerebral arteries; molecular analyses subsequently confirmed K
IR
2.1/K
IR
2.2 mRNA and protein expression in both cells. Patch-clamp electrophysiology next demonstrated that each population of K
IR
channels was sensitive to key membrane lipids and hemodynamic stimuli. In this regard, endothelial K
IR
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
IR
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
IR
channels was confirmed in intact arteries using myography. Virtual models integrating structural/electrical observations reconceptualized K
IR
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
IR
interactions enable unique channel populations to sense hemodynamic stimuli and drive vasomotor responses to set basal perfusion in the cerebral circulation.
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