Therapeutic Targets for Neurological Diseases 2015; 2: e476. doi: 10.14800/ttnd.476; © 2015 by Yukihiro Ohno, et al. http://www.smartscitech.com/index.php/ttnd Page 1 of 10 Role of astroglial Kir4.1 channels in the pathogenesis and treatment of epilepsy Yukihiro Ohno, Kentaro Tokudome, Naofumi Kunisawa, Higor A. Iha, Masato Kinboshi, Takahiro Mukai, Tadao Serikawa, Saki Shimizu Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1Nasahara, Takatsuki, Osaka 569-1094, Japan Correspondence: Yukihiro Ohno E-mail: yohno@gly.oups.ac.jp Received: December 10, 2014 Published online: January 03, 2015 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. Keywords: Astrocytes; EAST syndrome; Epilepsy; Generalized tonic-clonic seizures; Kir4.1 channels; SeSAME syndrome; Spatial potassium buffering To cite this article: Yukihiro Ohno, et al. Role of astroglial Kir4.1 channels in the pathogenesis and treatment of epilepsy. Ther Targets Neurol Dis 2015; 2: e476. doi: 10.14800/ttnd.476. Introduction Epilepsy is a serious neurological disorder that is clinically characterized by recurrent spontaneous seizures attributed to abnormal excitation of the brain [1, 2] . Epilepsy can be classified as generalized seizures (e.g., generalized tonic-clonic, absence and myoclonic seizures) and partial seizures (e.g., simple and complex focal seizures), depending on the epileptic foci involved. Various antiepileptic agents are available to treat epilepsy and the action mechanisms include the blockade of voltage-dependent sodium channels (e.g., sodium valproate, phenytoin, carbamazepine and lamotrigine), the activation of GABAergic neurotransmissionby inhibition of GABA transaminase (e.g., sodium valproate) or stimulation of GABA A receptors (e.g., phenobarbital and diazepam), the blockade of voltage-dependent calcium channels (e.g., gabapentin, lamotrigine and ethosuximide), or the antagonism of glutamate receptors (e.g., topiramate) [3] . However, these antiepileptic drugs often cause serious side effects (e.g., sedation, dizziness, Stevens-Johnson syndrome, toxic epidermal necrolysis and teratogenesis) and nearly one-third of patients with epilepsy are resistant to the current medications. Thus, there are strong clinical needs for the development of new medications or treatments for epilepsy. Brain neurotransmission is mediated by tripartite synapses which consist of not only neural (i.e., pre-synaptic terminals REVIEW