K_IR channels in the microvasculature: Regulatory properties and the lipid-hemodynamic environment

Basal tone and perfusion control is set in cerebral arteries by the sensing of pressure and flow, key hemodynamic stimuli. These forces establish a contractile foundation within arterial networks upon which local neurovascular stimuli operate. This fundamental process is intimately tied to arterial V_M and the rise in cytosolic [Ca²⁺] by the graded opening of voltage-operated Ca²⁺ channels. Arterial V_M is in turn controlled by a dynamic interaction among several resident ion channels, K_IR being one of particular significance. As the name suggests, K_IR displays strong inward rectification, retains a small outward component, potentiated by extracellular K⁺ and blocked by micromolar Ba²⁺. Cerebrovascular K_IR is unique from other K⁺ currents as it is present in both smooth muscle and endothelium yet lacking in classical regulatory modulation. Such observations have fostered the view that K_IR is nothing more than a background conductance, activated by extracellular K⁺ and which passively facilitates dilation. Recent work in cell model systems has; however, identified two membrane lipids, phosphatidylinositol 4,5-bisphosphate (PIP₂) and cholesterol, that interact with K_IR2.x, to stabilize the channel in the preferred open or silent state, respectively. Translating this unique form of regulation, recent studies have demonstrated that specific lipid-protein interactions enable unique K_IR populations to sense distinct hemodynamic stimuli and set basal tone. This review summarizes the current knowledge of vascular K_IR channels and how the lipid and hemodynamic impact their activity.