Variable loss of Kir4.1 channel function in SeSAME syndrome mutations

Tang, Xiaofang; Hang, Darwin; Sand, Andrea E.; Kofuji, Paulo

doi:10.1016/j.bbrc.2010.07.105

Cited by 43 publications

(51 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Tang et al 38 investigated most of the published SeSAME/ EAST mutations in HEK293 cells (G77R and the compound heterozygous mutations were not studied), and they showed decreases in current, qualitatively similar to our results. Although both our group and Reichold et al 37 saw a further decrease in fractional current when Kir5.1 was coexpressed with mutants in a 10:1 ratio, Tang et al 38 saw less of a decrease in current using a 1:1 coexpression ratio.…”

Section: Discussionsupporting

confidence: 89%

“…Although both our group and Reichold et al 37 saw a further decrease in fractional current when Kir5.1 was coexpressed with mutants in a 10:1 ratio, Tang et al 38 saw less of a decrease in current using a 1:1 coexpression ratio. This group also found that coexpression of the mutants 1:1 with WT led to "rescue" of all currents (including those arising from WT/C140R and WT/ R199X) to WT/WT levels, whereas we found reductions relative to WT/WT of 40% and 55%, respectively, for these two constructs ( Figure 3B).…”

Section: Discussionmentioning

confidence: 45%

“…Whether their use of green fluorescent protein-tagged channel subunits (versus our untagged constructs) or whether differences in expression system led to this discrepancy is unclear. Tang et al 38 also showed a representative blot of cell-surface biotinylated proteins probed with antigreen fluorescent protein antibody. No surface expression was seen with R199X, consistent with our data which suggested that R199X does not contribute to the formation of functional channels.…”

Section: Discussionmentioning

confidence: 99%

“…37,38 Reichold et al 37 studied R65P, G77R, R199X, and a new mutation, R175Q, in mammalian cell lines under patch clamp. They reported functional deficits similar to those described here, both when the mutants were expressed alone and when they were coexpressed with Kir5.1.…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Molecular Basis of Decreased Kir4.1 Function in SeSAME/EAST Syndrome

Williams¹,

Lopes

Rosenhouse‐Dantsker

et al. 2010

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

SeSAME/EAST syndrome is a channelopathy consisting of a hypokalemic, hypomagnesemic, metabolic alkalosis associated with seizures, sensorineural deafness, ataxia, and developmental abnormalities. This disease links to autosomal recessive mutations in KCNJ10, which encodes the Kir4.1 potassium channel, but the functional consequences of these mutations are not well understood. In Xenopus oocytes, all of the disease-associated mutant channels (R65P, R65P/R199X, G77R, C140R, T164I, and A167V/R297C) had decreased K ϩ current (0 to 23% of wild-type levels). Immunofluorescence demonstrated decreased surface expression of G77R, C140R, and A167V expressed in HEK293 cells. When we coexpressed mutant and wild-type subunits to mimic the heterozygous state, R199X, C140R, and G77R currents decreased to 55, 40, and 20% of wild-type levels, respectively, suggesting that carriers of these mutations may present with an abnormal phenotype. Because Kir4.1 subunits can form heteromeric channels with Kir5.1, we coexpressed the aforementioned mutants with Kir5.1 and found that currents were reduced at least as much as observed when we expressed mutants alone. Reduction of pH i from approximately 7.4 to 6.8 significantly decreased currents of all mutants except R199X but did not affect wild-type channels. In conclusion, perturbed pH gating may underlie the loss of channel function for the disease-associated mutant Kir4.1 channels and may have important physiologic consequences.

show abstract

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 45%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Molecular Basis of Decreased Kir4.1 Function in SeSAME/EAST Syndrome

Williams¹,

Lopes

Rosenhouse‐Dantsker

et al. 2010

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…"EAST" and "SeSAME" syndromes were reported independently by different groups, but consist mostly of identical symptoms: GTCS, ataxia, hearing loss and abnormal excretion of electrolytes ( Table 2). The most frequent mutation of KCNJ10 was R65P at the cytoplasmic end of the first transmembrane region (TM-1) and others include G77R (TM-1), C140R (extracellular loop between TM-1 and TM-2), T164I, A167V (cytoplasmic end of TM-2), R175Q, R199X and R297C (C-terminal domain) [50][51][52] . All these Kir4.1 mutations caused drastic decreases in K + buffering currents conducted not only by Kir4.1 channels, but also by Kir4.1/5.1 channels.…”

Section: Kir41 Channels and Human Epileptic Disordersmentioning

confidence: 99%

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

Ohno

Tokudome²,

Kunisawa³

et al. 2015

Ther Targets Neurol Dis

View full text Add to dashboard Cite

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.

show abstract

Distal Convoluted Tubule

McCormick

Ellison

2014

Comprehensive Physiology

View full text Add to dashboard Cite

The distal convoluted tubule (DCT) is a short nephron segment, interposed between the macula densa and collecting duct. Even though it is short, it plays a key role in regulating extracellular fluid volume and electrolyte homeostasis. DCT cells are rich in mitochondria, and possess the highest density of Na + /K + -ATPase along the nephron, where it is expressed on the highly amplified basolateral membranes. DCT cells are largely water impermeable, and reabsorb sodium and chloride across the apical membrane via electroneurtral pathways. Prominent among this is the thiazide-sensitive sodium chloride cotransporter, target of widely used diuretic drugs. These cells also play a key role in magnesium reabsorption, which occurs predominantly, via a transient receptor potential channel (TRPM6). Human genetic diseases in which DCT function is perturbed have provided critical insights into the physiological role of the DCT, and how transport is regulated. These include Familial Hyperkalemic Hypertension, the salt-wasting diseases Gitelman syndrome and EAST syndrome, and hereditary hypomagnesemias. The DCT is also established as an important target for the hormones angiotensin II and aldosterone; it also appears to respond to sympathetic-nerve stimulation and changes in plasma potassium. Here, we discuss what is currently known about DCT physiology. Early studies that determined transport rates of ions by the DCT are described, as are the channels and transporters expressed along the DCT with the advent of molecular cloning. Regulation of expression and activity of these channels and transporters is also described; particular emphasis is placed on the contribution of genetic forms of DCT dysregulation to our understanding.

show abstract

Variable loss of Kir4.1 channel function in SeSAME syndrome mutations

Cited by 43 publications

References 30 publications

Molecular Basis of Decreased Kir4.1 Function in SeSAME/EAST Syndrome

Molecular Basis of Decreased Kir4.1 Function in SeSAME/EAST Syndrome

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

Distal Convoluted Tubule

Contact Info

Product

Resources

About