Kir4.1 Potassium Channel Subunit Is Crucial for Oligodendrocyte Development and<i>In Vivo</i>Myelination

Neusch, Clemens; Rozengurt, Nora; Jacobs, Russell E.; Lester, Henry A.; Kofuji, Paulo

doi:10.1523/jneurosci.21-15-05429.2001

Cited by 286 publications

(359 citation statements)

References 40 publications

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“…Deletion of Kirs in mouse models has been shown to cause hypomyelination of white matter structures mimicking leukodystrophy, which is supportive with the multiple periventricular hyperdense lesions in our patient. 15 In our study, we found that the KCNJ2 T192I mutation is the genetic cause of ATS in our index family. T192I is located on the highly conserved region of the C-terminal intracellular domain of the Kir2.1 protein (Figure 1e), highlighting the importance of this residue in the evolution.…”

Section: Discussionmentioning

confidence: 52%

A novel neuropsychiatric phenotype of KCNJ2 mutation in one Taiwanese family with Andersen–Tawil syndrome

Chan

Chen

et al. 2010

J Hum Genet

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Andersen-Tawil syndrome (ATS) is a rare familial potassium channelopathy characterized by the clinical triad of periodic paralysis, cardiac arrhythmia and dysmorphic facial/skeletal features. The majority of ATS patients are caused by mutations of the KCNJ2 gene, which encodes the inward-rectifying potassium channel protein Kir2.1. However, the effects of the KCNJ2 mutation on the central nervous system are rarely studied. In this report, we describe a heterozygous missense mutation (p.Thr192Ile) in the KCNJ2 gene, which segregates with the disease phenotype in an ATS family. It is noted that in addition to the classical clinical phenotypes of ATS, the index patient exhibited major depression and pyramidal tract signs with diffuse periventricular white matter lesions without contrast enhancement. This mutation and the unusual clinical manifestations observed underscore the phenotypic complexity underlying ATS. Our observations expand the current knowledge of the phenotypic variability of ATS caused by the KCNJ2 mutation. Patients with ATS, especially those carrying the KCNJ2 mutations, should be monitored for their potential neuropsychiatric system involvement.

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Section: Discussionmentioning

confidence: 52%

A novel neuropsychiatric phenotype of KCNJ2 mutation in one Taiwanese family with Andersen–Tawil syndrome

Chan

Chen

et al. 2010

J Hum Genet

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“…Kir4.1 channel subunits, which conduct weakly inwardly rectifying currents in glia (Connors and Kofuji 2002;Kofuji and Newman 2004;Neusch et al 2006;Neusch et al 2001), have been suggested to play homeostatic roles within cochlear tissues (Hibino et al 1999;Hibino et al 1997;Marcus et al 2002;Rozengurt et al 2003;Takeuchi et al 2000). Consequently, we re-investigated the expression of Kir4.1 in the guinea pig cochlear lateral wall.…”

Section: Dye Transfer Reveals Intercellular Coupling and Tonotopic Vamentioning

confidence: 97%

“…5A and B), a blocker of currents carried by the K + channel subunit Kir4.1 in glia (Connors and Kofuji 2002;Neusch et al 2006;Neusch et al 2001). Application of Ba 2+ also caused depolarization of root cells ( Fig.…”

Section: Dye Transfer Reveals Intercellular Coupling and Tonotopic Vamentioning

confidence: 99%

The Membrane Properties of Cochlear Root Cells are Consistent with Roles in Potassium Recirculation and Spatial Buffering

Jagger

Nevill

Forge

2010

JARO

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Auditory transduction, amplification, and hair cell survival depend on the regulation of extracellular [K + ] in the cochlea. K + is removed from the vicinity of sensory hair cells by epithelial cells, and may be distributed through the epithelial cell syncytium, reminiscent of "spatial buffering" in glia. Hypothetically, K + is then transferred from the epithelial syncytium into the connective tissue syncytium within the cochlear lateral wall, enabling recirculation of K + back into endolymph. This may involve secretion of K + from epithelial root cells, and its re-uptake via transporters into spiral ligament fibrocytes. The molecular basis of this secretion is not known. Using a combination of approaches we demonstrated that the resting conductance in guinea pig root cells was dominated by K + channels, most likely composed of the Kir4.1 subunit. Dye injections revealed extensive intercellular gap junctional coupling, and delineated the root cell processes that penetrated the spiral ligament. Following uncoupling using 1-octanol, individual cells had Ba 2+ -sensitive weakly rectifying currents. In the basal (high-frequency encoding) cochlear region K + loads are predicted to be the highest, and root cells in this region had the largest surface area and the highest current density, consistent with their role in K + secretion. Kir4.1 was localized within root cells by immunofluorescence, and specifically to root cell process membranes by immunogold labeling. These results support a role for root cells in cochlear K + regulation, and suggest that channels composed of Kir4.1 subunits may mediate K + secretion from the epithelial gap junction network.

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“…Global knockout of Kir4.1 leads to postnatal lethality (Neusch, Rozengurt, Jacobs, Lester, & Kofuji, 2001), whereas conditional Kir4.1 knockout in astrocytes alone is able to trigger epilepsy (Chever, Djukic, McCarthy, & Amzica, 2010; Haj‐Yasein et al, 2011a). In the same vein, mutations or single nucleotide polymorphisms in the genes encoding Kir4.1 are associated with human epilepsy (Bedner and Steinhauser.…”

Section: Astrocytes In the Diseased Brain Are Central To Neuropathologymentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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Kir4.1 Potassium Channel Subunit Is Crucial for Oligodendrocyte Development andIn VivoMyelination

Cited by 286 publications

References 40 publications

A novel neuropsychiatric phenotype of KCNJ2 mutation in one Taiwanese family with Andersen–Tawil syndrome

A novel neuropsychiatric phenotype of KCNJ2 mutation in one Taiwanese family with Andersen–Tawil syndrome

The Membrane Properties of Cochlear Root Cells are Consistent with Roles in Potassium Recirculation and Spatial Buffering

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

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