The role of glial-specific Kir4.1 in normal and pathological states of the CNS

Sinifunanya E. Nwaobi, Vishnu A. Cuddapah, Kelsey C. Patterson, Anita C. Randolph, Michelle L. Olsen

Research output: Contribution to journalReview articlepeer-review

66 Scopus citations

Abstract

Kir4.1 is an inwardly rectifying K+ channel expressed exclusively in glial cells in the central nervous system. In glia, Kir4.1 is implicated in several functions including extracellular K+ homeostasis, maintenance of astrocyte resting membrane potential, cell volume regulation, and facilitation of glutamate uptake. Knockout of Kir4.1 in rodent models leads to severe neurological deficits, including ataxia, seizures, sensorineural deafness, and early postnatal death. Accumulating evidence indicates that Kir4.1 plays an integral role in the central nervous system, prompting many laboratories to study the potential role that Kir4.1 plays in human disease. In this article, we review the growing evidence implicating Kir4.1 in a wide array of neurological disease. Recent literature suggests Kir4.1 dysfunction facilitates neuronal hyperexcitability and may contribute to epilepsy. Genetic screens demonstrate that mutations of KCNJ10, the gene encoding Kir4.1, causes SeSAME/EAST syndrome, which is characterized by early onset seizures, compromised verbal and motor skills, profound cognitive deficits, and salt-wasting. KCNJ10 has also been linked to developmental disorders including autism. Cerebral trauma, ischemia, and inflammation are all associated with decreased astrocytic Kir4.1 current amplitude and astrocytic dysfunction. Additionally, neurodegenerative diseases such as Alzheimer disease and amyotrophic lateral sclerosis demonstrate loss of Kir4.1. This is particularly exciting in the context of Huntington disease, another neurodegenerative disorder in which restoration of Kir4.1 ameliorated motor deficits, decreased medium spiny neuron hyperexcitability, and extended survival in mouse models. Understanding the expression and regulation of Kir4.1 will be critical in determining if this channel can be exploited for therapeutic benefit.

Original languageEnglish (US)
JournalActa Neuropathologica
Volume132
Issue number1
DOIs
StatePublished - Jul 1 2016
Externally publishedYes

Fingerprint Dive into the research topics of 'The role of glial-specific Kir4.1 in normal and pathological states of the CNS'. Together they form a unique fingerprint.

Cite this