**3.3 Kir channels**

As their name implies, Kir channels produce an inward current. This current is observed at a potential negative to the K+ equilibrium potential that helps stabilize the resting Em [1, 66]. They also produce a small outward current at depolarizing potentials that serves as an electrical amplifier to magnify hyperpolarization. Inward rectification occurs due to voltage-dependent blockade of the channel by polyamines and Mg2+. Kir channels are regulated by lipids (e.g., phosphatidylinositol 4,5 bisphosphate (PIP2) and cholesterol) [1, 66]. Intriguingly, a recent study found that cholesterol, but not PIP2, regulates Kir channel activity in the cerebral

vascular smooth muscle [67], suggesting that these channels may be distinctively modulated by lipids depending on their tissue distribution. A functional Kir channel is formed when four pore-forming α subunits, each containing two membranespanning domains, come together. Two main α subunits (e.g., Kir2.1 and Kir2.2) have been identified in vascular smooth muscle from multiple species [68–71]. Intriguingly, the expression of these subunits in a specific vascular bed may be species-dependent. Accordingly, although Kir subunit expression and channel activity have been extensively reported in murine cerebral vascular smooth muscle [67–69, 71], minimal, if any, Kir subunit expression and channel activity were found in the human cerebral vascular smooth muscle [72]. The functional implication of the activation of these channels in vascular smooth muscle is relaxation. Kir channel activity can be modulated by vasoactive agents with those acting through the Gq/PLC/PKC axis, inducing channel inhibition, and those acting on the Gs/AC/ PKA pathway, promoting channel activity [1]. The physiological relevance of these regulatory mechanisms on Kir channels and their control of vascular function are less well understood and therefore are in need of further evaluation.
