Dual contribution of NR2B subunit of NMDA receptor and SK3 Ca2+-activated K+ channel to genetic predisposition to anorexia nervosa

Koronyo‐Hamaoui, Maya; Frisch, Amos; Stein, Daniel; Denziger, Yardena; Leor, Shani; Michaelovsky, Elena; Laufer, Neil; Carel, Cynthia A.; Fennig, Silvana; Mimouni, M.; Ram, Alpana; Zubery, Eynat; Jeczmien, Pablo; Apter, Alan; Weizman, Abraham; Gak, Eva

doi:10.1016/j.jpsychires.2005.07.010

Cited by 24 publications

(14 citation statements)

References 46 publications

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“…In humans, polymorphisms on the gene encoding the SK3 channel have been associated with neuropsychiatric disorders characterized by emotional dysregulation including schizophrenia, bipolar disorder, and anorexia nervosa (Chandy et al, 1998; Koronyo-Hamaoui et al, 2007; Grube et al, 2011). Administration of the SK channel blocker apamin in mice and rats reduced immobility in a forced swim test (Galeotti et al, 1999; van der Staay et al, 1999), a measure of depressive-like behavior in rodents (Cryan and Slattery, 2007).…”

Section: Discussionmentioning

confidence: 99%

Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels

Sargin

Oliver

Lambe

2016

eLife

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The activity of serotonin (5-HT) neurons is critical for mood regulation. In a mouse model of chronic social isolation, a known risk factor for depressive illness, we show that 5-HT neurons in the dorsal raphe nucleus are less responsive to stimulation. Probing the responsible cellular mechanisms pinpoints a disturbance in the expression and function of small-conductance Ca2+-activated K+ (SK) channels and reveals an important role for both SK2 and SK3 channels in normal regulation of 5-HT neuronal excitability. Chronic social isolation renders 5-HT neurons insensitive to SK2 blockade, however inhibition of the upregulated SK3 channels restores normal excitability. In vivo, we demonstrate that inhibiting SK channels normalizes chronic social isolation-induced anxiety/depressive-like behaviors. Our experiments reveal a causal link for the first time between SK channel dysregulation and 5-HT neuron activity in a lifelong stress paradigm, suggesting these channels as targets for the development of novel therapies for mood disorders.DOI: http://dx.doi.org/10.7554/eLife.21416.001

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Section: Discussionmentioning

confidence: 99%

Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels

Sargin

Oliver

Lambe

2016

eLife

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“…The authors do not have any conflicts of interest to report. 22 Supplemental Table 1. Descriptions of the male and female rhesus macaques used in these studies.…”

Section: Conflict Of Interestmentioning

confidence: 99%

“…There are two polymorphic CAG repeats in the N-terminus of human KCNN3 encoded by exon 1 (18). Higher numbers of CAG repeats reduced KCa2 channel function in transfected HEK293 cells (19), and this polymorphism has been associated with neuropsychiatric conditions, such as schizophrenia and anorexia nervosa (18,(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcript variants by excessive ethanol drinking and dependence

Cervera-Juanes

Padula

Wilhem

et al. 2019

Preprint

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The underlying genetic and epigenetic mechanisms driving functional adaptations in neuronal excitability and excessive alcohol intake are poorly understood. Given that small-conductance Ca 2+ -activated K + (KCa2 or SK) channels encoded by the KCNN family of genes have emerged from preclinical studies as a crucial target that contributes to heavy drinking and alcohol-induced functional neuroadaptations, we performed a cross-species analysis of KCNN3 methylation, gene expression, and polymorphisms of alcohol-drinking monkeys and alcohol dependent mice. Because of the alternative promoters in KCNN3, we analyzed expression of the different transcript variants that when translated influence surface trafficking and function of KCa2 channels. In heavy drinking rhesus macaques and alcohol dependent C57BL/6J mice, bisulfite sequencing analysis of the nucleus accumbens revealed a differentially methylated region in exon 1A of KCNN3 that overlaps with a predicted promoter sequence. The hypermethylation of KCNN3 in monkey and mouse accumbens paralleled an increase in expression of alternative transcript variants that encode apamin-insensitive and dominant-negative KCa2 channel isoforms. A polymorphic repeat in macaque KCNN3 encoded by exon 1 did not correlate with alcohol drinking. At the protein level, KCa2.3 channel expression in the accumbens was significantly reduced in very heavy drinking monkeys. Together, our cross-species findings on epigenetic dysregulation of KCNN3 by heavy alcohol drinking and dependence represent a complex mechanism that utilizes alternative promoters to impact firing of accumbens neurons. Thus, these results provide support for hypermethylation of KCNN3 by excessive alcohol drinking as a possible key molecular mechanism underlying harmful alcohol intake and alcohol use disorder.

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“…In any case, the main pathways involved in eating behavior could be roughly summarized in central neurotransmission, especially serotonin, dopamine and, to lesser extent, noradrenaline, whose involvement in ED has been extensively studied; reward-related pathways, particularly the cannabinoid endogenous system (it has been suggested that AN patients have a dysregulation of this Obesity-associated genes in the etiopathogenesis of eating disorders Perspective system and that restriction and exercise become a way to compensate for diminished response to reward [39]) and central regulation of food intake, including ghrelin, an appetite-stimulating hormone that functions as a neuropeptide in the CNS and whose levels may be altered in women with AN [40]. In addition, a variety of other genes that do not strictly fit in this classification have been tested in genetic association studies with ED patients, albeit with generally inconsistent results [41][42][43][44][45][46][47][48][49].…”

Section: Candidate Genes In Biological Pathways Involved In Eating DImentioning

confidence: 99%

Discussing the Putative Role of Obesity-Associated Genes in the Etiopathogenesis of Eating Disorders

Gervasini

Gamero-Villarroel

2015

Pharmacogenomics

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In addition to the identification of mutations clearly related to Mendelian forms of obesity; genome-wide association studies and follow-up studies have in the last years pinpointed several loci associated with BMI. These genetic alterations are located in or near genes expressed in the hypothalamus that are involved in the regulation of eating behavior. Accordingly, it seems plausible that these SNPs, or others located in related genes, could also help develop aberrant conduct patterns that favor the establishment of eating disorders should other susceptibility factors or personality dimensions be present. However, and somewhat surprisingly, with few exceptions such as BDNF, the great majority of the genes governing these pathways remain untested in patients with anorexia nervosa, bulimia nervosa or binge-eating disorder. In the present work, we review the few existing studies, but also indications and biological concepts that point to these genes in the CNS as good candidates for association studies with eating disorder patients.

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Dual contribution of NR2B subunit of NMDA receptor and SK3 Ca2+-activated K+ channel to genetic predisposition to anorexia nervosa

Cited by 24 publications

References 46 publications

Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels

Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels

Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcript variants by excessive ethanol drinking and dependence

Discussing the Putative Role of Obesity-Associated Genes in the Etiopathogenesis of Eating Disorders

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