Astrocytic Kir4.1 potassium channels as a novel therapeutic target for epilepsy and mood disorders

Yukihiro Ohno

doi:10.4103/1673-5374.230355

摘要：Astrocytic Kir4.1 channels and spatial potassium buffering: Astro-cytes play a crucial role in maintaining the structural and functional integrity of the brain, which includes formation of the blood-brain barrier, maintenance of water and ion homeostasis, metabolism of neurotransmitters and secretion of various neuroactive molecules. Among these functions, spatial potassium (K+) buffering by astro-cytes is an essential system for controlling extracellular K+con-centration ([K+]o) and neuronal excitability (Figure 1) (Kofuji and Newman, 2004; Ohno et al., 2015). Neurons normally release con-siderable amounts of K+during the repolarization phase of an action potential. At tripartite synapses, a single action potential elevates the local [K+]olevel by about 1 mM and, if uncorrected, [K+]oreaches 10 mM or more, causing abnormal discharges and finally spreading de-pression. Spatial K+buffering by astrocytes is a K+-clearance system which removes an excess of extracellular K+and transports it to the regions of low [K+]osuch as capillary vessels (Figure 1). In addition, the spatial K+buffering system is coupled to astrocytic glutamate up-take by glutamate transporters (e.g., EAAT1 and EAAT2) and water transport by aquaporin-4 (AQP4) (Kofuji and Newman, 2004; Ohno et al., 2015).Spatial K+buffering is mainly mediated by two types of inwardly rectifying K+(Kir) channels, Kir4.1 channels (homo-tetramer of Kir4.1 subunits) and Kir4.1/5.1 channels (hetero-tetramer of Kir4.1 and Kir5.1 subunits) (Figure 1). Kir4.1 and Kir5.1 subunits consist of 379 and 418 amino acids, respectively, and possess two transmem-brane-spanning (TM) structures, which form the pore–region of the Kir4.1-containing channels (Ohno et al., 2015). Kir4.1 and Kir4.1/5.1 channels constitutively allow large inward K+currents at potentials negative to K+equilibrium potential (EK) and small, but significant, outward K+currents at those positive to EK(Kofuji and Newman, 2004). Therefore, they can absorb excessive extracellular K+locally elevated at synapses and transport it to sites with low K+concentra-tions, depending on the difference between local EKand the mem-brane potential of astrocytes. Thus, Kir4.1 and Kir4.1/5.1 channels directly influence the spatial K+buffering capacity of astrocytes and dysfunction of these channels causes an excitation of neurons by elevating the [K+]oand extracellular glutamate ([glutamate]o) levels (Figure 1) (Djukic et al., 2007; Ohno et al., 2015).