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 K(+) ions are rapid and potent vasodilators that increase 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 NVC. It has been proposed that the activation of 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 KIR 2 subtype in particular, are present in both the endothelial and SM cells of parenchymal arterioles and propose that this dual positioning of KIR 2 channels increases the robustness of the vasodilation to external K(+), enables the endothelium to be actively engaged in NVC, and permits electrical signaling through the endothelial syncytium to promote upstream vasodilation to modulate CBF.

Keywords: astrocytic endfoot; capillary; cerebral blood flow; endothelium; functional hyperemia; inward rectifier potassium channel; neurovascular coupling; parenchymal arteriole; smooth muscle.

Figure 1

K⁺ signaling mechanisms in NVC. K⁺-mediated dilation (left) begins with neuronal activity which is detected by astrocytic processes adjacent to synapses leading to phospholipase C (PLC)-mediated liberation of inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG) from membrane phosphatidylinositol 4,5-bisphosphate (PIP₂) pools, ultimately resulting in an IP_3-mediated Ca²⁺ wave which propagates into astrocytic endfeet enwrapping the cerebral microcirculation [115]. This engages large-conductance calcium (Ca²⁺)-activated K⁺ (BK) channels on the endfoot plasma membrane [26,27,97], and their activation leads to an increase in the concentration of K⁺ in the extracellular nanospace between the endfoot and SM. The rise in external K⁺ activates strong inward-rectifier K⁺ (K_IR) channels on the smooth muscle, leading to membrane hyperpolarization, closure of voltage-dependent Ca²⁺ channels, vasorelaxation and increased blood flow [26]. During more intense neuronal activity (right), larger Ca²⁺ waves promote the release of higher concentrations of K⁺ from the endfoot, leading to membrane depolarization, VDCC activation and constriction [27]. Under both conditions, the Na⁺/K⁺ ATPase likely contributes to K⁺ clearance and may provide a brief accompanying hyperpolarizing current. Adapted from [67] and [27].

Figure 2

Inward-rectifier K⁺ channels are activated by increases in external K⁺. (A) In situ, raising K⁺ to <20 mM causes rapid and substantial vasodilation of pressurized (40 mm Hg) PAs due to K_IR channel activation; further increases in K⁺ drive membrane depolarization and constriction. Trace from [67]. (B) The SM of PAs behaves as a K⁺ electrode with increasing concentrations of extracellular K⁺. Experimentally observed membrane potential (V_m) data (from [26,37,89]) are shown versus the potassium equilibrium potential (E_K) predicted by the Nernst equation. At 3 mM K⁺, V_m is depolarized relative to E_K due to myogenic inward cation currents. Raising K⁺ activates K_IR channels, and the resultant K⁺ efflux effectively locks V_m at E_K. (C) Hypothetical K_IR current-voltage relationship (left) and illustration (right) showing that at basal extracellular K⁺ (3 mM) the pore of the K_IR channel is blocked by Mg²⁺ or large cationic polyamines. Under these conditions (assuming 140 mM [K⁺]_i), E_K is -103, which is highly negative compared to the resting V_m of SM (approximately -35 to -40 mV) at the physiological intravascular pressure of 40 mmHg. The strong driving force for cation efflux under these conditions leads to blockade of the channel pore by the larger cations, resulting in very little channel activity. (D) When [K⁺]_o is elevated to 8 mM (e.g., when released from the astrocytic endfoot during NVC), intracellular blockade of the channel is relieved. Channel unblock allows K⁺ to exit the cell, driving V_m to the new E_K—where it will remain until the extracellular K⁺ is cleared—and leading to substantial vasodilation.

Figure 3

(A) K_IR channel conductance over a range of V_m values with increasing concentrations of K⁺. With 3 mM [K⁺] _o at -40 mV (the approximate resting V_m; dotted arrows), K_IR channel conductance is very low. Raising K⁺ greatly increases K_IR channel activity at a given V_m; channel activity is also increased by membrane hyperpolarization. Data were plotted according to the eq. 1 in the text. (B) The relationship between external K⁺ concentration and K_IR channel conductance based on the K⁺- and voltage-dependence of K_IR2 channels, calculated using eq. 1 (see text), and measured effects of external K⁺ on PA SM V_m [26,37]. Elevation of [K⁺]_o from 3 mM to 8 mM causes an enormous, near-maximal increase in K_IR channel conductance, with further elevations to 15 and 25 mM causing only small subsequent increases in conductance. (C) Subtracted 100-μM Ba²⁺-sensitive currents from a freshly dissociated EC from a rat PA in response to a voltage ramp from -140 to 0 mV indicating the presence of functional K_IR2 channels in these cells. External K⁺ was 6 mM in this experiment.

Figure 4

Proposed scheme for K_IR channels as K⁺ sensors to control cerebral blood flow. K⁺ ions released from astrocytic endfeet and neurons activates K_IR2 channels present on SM cells and ECs in PAs and (possibly) on capillary ECs. Hyperpolarization caused by K_IR engagement may then spread bi-directionally throughout the vascular syncytium, causing further K_IR channel activation while at the same time deactivating K_V and BK channels and VDCCs in the SM. This locks the membrane potential at E_K until K⁺ is cleared and causes near maximal vasodilation and a substantial increase in cerebral blood flow.