Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

Abstract

ATP-sensitive potassium (K(ATP)) channels are weak, inward rectifiers that couple metabolic status to cell membrane electrical activity, thus modulating many cellular functions. An increase in the ADP/ATP ratio opens K(ATP) channels, leading to membrane hyperpolarization. K(ATP) channels are ubiquitously expressed in neurons located in different regions of the brain, including the hippocampus and cortex. Brief hypoxia triggers membrane hyperpolarization in these central neurons. In vivo animal studies confirmed that knocking out the Kir6.2 subunit of the K(ATP) channels increases ischemic infarction, and overexpression of the Kir6.2 subunit reduces neuronal injury from ischemic insults. These findings provide the basis for a practical strategy whereby activation of endogenous K(ATP) channels reduces cellular damage resulting from cerebral ischemic stroke. K(ATP) channel modulators may prove to be clinically useful as part of a combination therapy for stroke management in the future.

Figure 1

A schematic illustration showing the proposed structure of a K_ATP channel in neurons. The K_ATP channel is a hetero-octamer comprising two subunits: four pore-forming Kir6.2 subunits and four regulatory sulfonylurea receptor (SUR) subunits.

Figure 2

Schematic illustration of K_ATP channels function in neurons. K_ATP channels serve as metabolic sensors to couple electrical activity of neurons. Under normal physiological conditions, K_ATP channels remain closed due to the high ATP/ADP ratio. Reducing the ATP/ADP ratio by either decreasing ATP levels or enhancing ADP levels opens the channel and allows K⁺ ions to exit the cells, thus hyperpolarizing the neurons. SUR, sulfonylurea receptor.

Figure 3

Opening of K_ATP channels lead to K⁺ ion efflux and hyperpolarization of the cell membrane, resulting in a decrease in cell excitability. This hyperpolarization occurs by making the membrane potential more negative, which brings it towards the potassium equilibrium potential (E_K). Hyperpolarization suppresses and inhibits cell excitability.