Kir4.1 channels in NG2-glia play a role in development, potassium signaling, and ischemia-related myelin loss

Abstract

The contribution of the inwardly rectifying K+ channel subtype Kir4.1 has been focused mainly on astrocytes, where they play important roles in the maintenance of resting membrane potential, extracellular K+ uptake, and facilitation of glutamate uptake in the central nervous system. Here, we report the role of Kir4.1 channels in NG2-glia during brain development, potassium signaling, and in an ischemic stroke disease model. Kir4.1 channels are widely expressed in NG2-glia during brain development. In the adult mouse hippocampus, Kir4.1 channels in NG2-glia constitute more than 80% of K+ channels inward currents. This large portion of Kir4.1 channel currents exhibits a deficit in NG2-glia as an initial response in a transient ischemic mouse model. Further evidence indicates that Kir4.1 deficits in NG2-glia potentially cause axonal myelin loss in ischemia through the association with oligodendrocyte-specific protein (OSP/Claudin-11), which unravels a potential therapeutic target in the treatment of ischemic stroke.

Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

“…In addition to neurotrophic factors, neuropoetic cytokines and growth factors, astrocytes secrete a plethora of other protective factors, including cytokines, metabolites, extracellular matrix (ECM) proteins, and metalloproteinases (MMPs) (23,50,266,267,270). In the healthy brain, tight metabolic coupling between neurons and astrocytes is key to sustain high firing rates and neuronal wellbeing (267).…”

“…In this context, the inward rectifying K + channel Kir4.1 has gained attention as part of a K + spatial buffering system that is required for neuronal transmission and functioning ( Figure 1B). Kir4.1 is highly expressed in astrocytic endfeet, and its misregulation has been linked to numerous neurological disorders (21)(22)(23).…”

Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance

“…Depending on tissue localization and assembly of Kir4.1 subunit, these channels exhibit distinctive physiological properties [24]. Kir4.1 channel play conspicuous roles in a spectrum of biological contexts like maintenance of resting membrane potential [25], facilitation of glutamate uptake [26], potassium siphoning by glial cells [27,28], cell volume and peak strength regulation of motor neurons [10], axonal integrity through myelination by oligodendrocytes [6,7,29], and cell migration [9]. How Kir4.1 drives specific downstream signaling during disease manifestation in SeSAME syndrome requires us to understand the plethora of modifiers.…”

Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance

“…SeSAME syndrome (OMIM#612780), characterized by Seizures, Sensorineural deafness, Ataxia, Mental retardation and Electrolyte imbalance is a rare, autosomal recessive and multisystemic disorder. Otherwise known as EAST (Epilepsy, Ataxia, Sensorineural deafness, Tubulopathy) syndrome, SeSAME is predominantly caused by homozygous or compound heterozygous mutations in KCNJ10 gene (Bockenhauer et al, 2009;Scholl et al, 2009) encoding Kir4.1, an inwardly rectifying potassium channel with diverse expression patterns in multiple cell types of central and peripheral nervous system (Reichold et al, 2010;Hibino et al, 2010;Paulais et al, 2011;Thompson et al, 2011;Kelley et al, 2018;Larson et al, 2018;Song et al, 2018). Depending on tissue localization and assembly of Kir4.1 subunit, which can constitute homotetramers and/or heterotetramers with Kir5.1 (KCNJ16), these channels exhibit distinctive physiological properties (Paulais et al, 2011;Pessia et al, 2001).…”

“…Depending on tissue localization and assembly of Kir4.1 subunit, which can constitute homotetramers and/or heterotetramers with Kir5.1 (KCNJ16), these channels exhibit distinctive physiological properties (Paulais et al, 2011;Pessia et al, 2001). Kir4.1 channel play conspicuous roles in the maintenance of resting membrane potential (Kofuji et al, 2000), facilitation of glutamate uptake (Djukic et al, 2007), potassium siphoning by glial cells (Neusch et al, 2006;Song et al, 2018), cell volume and peak strength regulation of fast α-motor neurons (FαMNs; Kelley et al, 2018), axonal integrity through myelination by oligodendrocytes (Neusch et al, 2001;Schirmer et al, 2018;Larson et al, 2018) and cell migration (dehart et al, 2008). Dysfunction of Kir4.1 has been associated with a spectrum of neurodegenerative conditions like idiopathic epilepsy (Buono et al, 2004;Heuser et al, 2010;Lenzen et al, 2005), autism spectrum disorder with seizures (Sicca et al, 2011;Sicca et al, 2016;Larson et al, 2018), Huntington's disease (Tong et al, 2014), multiple sclerosis (Srivatsava et al, 2012;Brickshawana et al, 2014;Nwaobi et al, 2016;Gu et al, 2016) and Rett syndrome (Olsen et al, 2015;Kahanovitch et al, 2018).…”