Role of astroglial Kir4.1 channels in the pathogenesis and treatment of epilepsy

Abstract

The inwardly rectifying potassium (Kir) channel subunit Kir4.1 is specifically expressed in brain astrocytes and Kir4.1-containing channels (Kir4.1 channels) mediate astroglial spatial potassium (K + ) buffering. Recent advances in Kir4.1 research revealed that Kir4.1 channels can serve as a novel therapeutic target for epilepsy. Specifically, reduced expression or dysfunction of Kir4.1 channels seems to be involved in generation of generalized tonic-clonic seizures (GTCS) in animal models of epilepsy and patients with temporal lobe epilepsy. In addition, recent clinical studies showed that loss-of-function mutations of human gene (KCNJ10) encoding Kir4.1 elicit "EAST" or "SeSAME" syndrome which manifests as GTCS and ataxia. Although the precise mechanisms remain to be clarified, it is suggested that dysfunction of Kir4.1 channels disrupts spatial K + buffering by astrocytes, elevates extracellular levels of K + and/or glutamate and causes abnormal excitation of neurons in the limbic regions and neocortex. All these findings suggest that agents that activate or up-regulate astroglial Kir4.1 channels would be effective for epilepsy. In addition, docking simulation analysis using the Kir4.1 homology model provides important information for designing new Kir4.1 ligands. Discovery of such agents that activate or up-regulate Kir4.1 channels would be a novel approach for the treatment of epilepsy.

Down-Regulation of Astrocytic Kir4.1 Channels during the Audiogenic Epileptogenesis in Leucine-Rich Glioma-Inactivated 1 (Lgi1) Mutant Rats

“…The present results suggested that the reduced expression of astrocytic Kir4.1 expression is involved in Lgi1-related epileptic disorders. The dysfunction of astrocytic Kir4.1 channels elevates the extracellular levels and K + and glutamate by suppressing the special K + buffering function of astrocytes, which increases the excitability of neurons [4,5,6,7]. In addition, we previously showed that down-regulation of the Kir4.1 channel expression enhanced the expression of BDNF, which is a key modulator of epileptogenesis, in astrocytes [18,19].…”

“…Specifically, the spatial potassium (K + ) buffering by astrocytes’ functions is a clearance mechanism of excessive extracellular K + secreted from excited neurons, and is essential for controlling neuronal excitability. If astrocytic K + buffering is disrupted, it increases the extracellular levels of K + and glutamate at the synapses, and causes the abnormal excitation of neurons [4,5,6,7].…”

“…Spatial K + buffering currents in astrocytes are primarily conducted by the inwardly rectifying K + (Kir) channels containing Kir4.1 subunits (Kir4.1 channels), which consist of Kir4.1 homotetramer and Kir4.1/5.1 heterotetramer channels [7,8]. Previous studies using conditional knockout mice have shown that the specific deletion of Kir4.1 in astrocytes depolarized their resting membrane potential and markedly reduced the transport capacity of K + and glutamate into astrocytes, causing ataxia, epileptic symptoms, and early mortality [9].…”

Role of Astrocytic Inwardly Rectifying Potassium (Kir) 4.1 Channels in Epileptogenesis

“…Specifically, astrocytes regulate ion homeostasis and extracellular space volume, metabolize neurotransmitters (e.g., glutamate, GABA, and glycine), and secrete various neuroactive molecules including gliotransmitters [e.g., glutamate, D-serine, adenosine 5 ′ -triphosphate (ATP)], neurotrophic factors [e.g., brain-derived neurotrophic factor (BDNF) and glia-derived neurotrophic factor (GDNF)], and cytokines [e.g., tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)] (11)(12)(13). Among these functions of astrocytes, a spatial buffering system for potassium ions (K + ) plays an important role in the maintenance of neuronal excitability, which transports excessive extracellular K + secreted from excited neurons to sites with lower K + concentrations (e.g., microcapillaries) (14)(15)(16)(17)(18). This potassium clearance mechanism is primarily mediated by astrocytic inwardly rectifying potassium (Kir) channels containing Kir4.1 subunits (Kir4.1 channels) (16)(17)(18)(19)(20)(21).…”

“…Among these functions of astrocytes, a spatial buffering system for potassium ions (K + ) plays an important role in the maintenance of neuronal excitability, which transports excessive extracellular K + secreted from excited neurons to sites with lower K + concentrations (e.g., microcapillaries) (14)(15)(16)(17)(18). This potassium clearance mechanism is primarily mediated by astrocytic inwardly rectifying potassium (Kir) channels containing Kir4.1 subunits (Kir4.1 channels) (16)(17)(18)(19)(20)(21).…”