Vascular Inward Rectifier K⁺ Channels as External K⁺ Sensors in the Control of Cerebral Blood Flow

Abstract

For decades it has been known that external potassium (K+) ions are rapid and potent vasodilators that increase cerebral blood flow (CBF). Recent studies have implicated the local release of K+ from astrocytic endfeet—which encase the entirety of the parenchymal vasculature—in the dynamic regulation of local CBF during neurovascular coupling (NVC). It has been proposed that the activation of strong inward rectifier K+ (KIR) channels in the vascular wall by external K+ is a central component of these hyperemic responses; however, a number of significant gaps in our knowledge remain. Here, we explore the concept that vascular KIR channels are the major extracellular K+ sensors in the control of CBF. We propose that K+ is an ideal mediator of NVC, and discuss KIR channels as effectors that produce rapid hyperpolarization and robust vasodilation of cerebral arterioles. We provide evidence that KIR channels, of the KIR2 subtype in particular, are present in both the endothelial and smooth muscle cells of parenchymal arterioles and propose that this dual positioning of KIR2 channels increases the robustness of the vasodilation to external K+, enables the endothelium to be actively engaged in neurovascular coupling, and permits electrical signaling through the endothelial syncytium to promote upstream vasodilation to modulate CBF.

Neuronal networks and mediators of cortical neurovascular coupling responses in normal and altered brain states

“…Recent reviews on NVC mechanisms have focused on neurons [30][31][32], astrocytes [10,[32][33][34][35], pericytes [36], on endothelial [37] and smooth muscle cells [12,38,39], and on their mediators [10,32,40]. Here, we will address NVC in the context of an integrated response to changes in the activity of a neuronal network.…”

Ion channel networks in the control of cerebral blood flow

“…26 Thus, the SM V m is quite positive to the K þ equilibrium potential (E K ), which is approximately À103 mV in CSF (assuming 3 mM extracellular K þ and 140 mM intracellular K þ ). These basal conditions mean that the activation of K þ channels can impart a major hyperpolarizing influence on cerebral SM, and thereby exert rapid and robust control over vascular diameter.…”

“…22 For this to occur, K þ permeability has to increase more than 50-fold; this is achieved through activation of SM inwardly rectifying K þ (K IR ) channels. 26 K IR channels, which form tetramers composed of two-transmembrane a-subunits, can be distinguished by their rectification properties. 72 The K IR subtypes expressed in parenchymal arterioles have yet to be definitively established, but the pharmacological sensitivity of the parenchymal SM K IR current to Ba 2þ ions in situ 22,28 is consistent with the presence of functional K IR 2-containing channels.…”

Inhibition of vascular smooth muscle inward-rectifier K+channels restores myogenic tone in mouse urinary bladder arterioles

“…A depolarized resting potential relative to E K sets the stage for activation of K IR channels by external K ϩ to cause membrane potential hyperpolarization, provided that E K remains negative to the resting potential; E K would be at a resting potential of Ϫ40 mV when external K ϩ is~25 mM (32,44,46). Thus changes in extracellular K ϩ concentration and membrane potential synergistically increase K IR channel conductance to hyperpolarize smooth muscle cells, ultimately causing vasodilation (33). This phenomenon is apparent in cerebral arteries, where members of the K IR 2 subfamily, specifically K IR 2.1, are expressed in smooth muscle and are involved in the regulation of arterial diameter and membrane potential (11,33,52).…”

“…Thus changes in extracellular K ϩ concentration and membrane potential synergistically increase K IR channel conductance to hyperpolarize smooth muscle cells, ultimately causing vasodilation (33). This phenomenon is apparent in cerebral arteries, where members of the K IR 2 subfamily, specifically K IR 2.1, are expressed in smooth muscle and are involved in the regulation of arterial diameter and membrane potential (11,33,52).…”