Endoplasmic reticulum potassium–hydrogen exchanger and small conductance calcium-activated potassium channel activities are essential for ER calcium uptake in neurons and cardiomyocytes

Kuum, Malle; Veksler, Vladimir; Liiv, Joanna; Ventura‐Clapier, Renée; Kaasik, Allen

doi:10.1242/jcs.090126

Cited by 50 publications

(47 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…38 Its cellular function as an ion exchanger [37][38][39][40][41] suggests potential roles in cell signaling and energy production. In flies and worms, LETM1 loss-of-function causes severe growth restriction and decreased viability.…”

Section: Discussionmentioning

confidence: 99%

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

et al. 2013

View full text Add to dashboard Cite

Wolf-Hirschhorn syndrome (WHS) is a complex genetic disorder caused by the loss of genomic material from the short arm of chromosome 4. Genotype-phenotype correlation studies indicated that the loss of genes within 4p16.3 is necessary for expression of the core features of the phenotype. Within this region, haploinsufficiency of the genes WHSC1 and LETM1 is thought to be a major contributor to the pathogenesis of WHS. We present clinical findings for three patients with relatively small (o400 kb) de novo interstitial deletions that overlap WHSC1 and LETM1. 3D facial analysis was performed for two of these patients. Based on our findings, we propose that hemizygosity of WHSC1 and LETM1 is associated with a clinical phenotype characterized by growth deficiency, feeding difficulties, and motor and speech delays. The deletion of additional genes nearby WHSC1 and LETM1 does not result in a marked increase in the severity of clinical features, arguing against their haploinsufficiency. The absence of seizures and typical WHS craniofacial findings in our cohort suggest that deletion of distinct or additional 4p16.3 genes is necessary for expression of these features. Altogether, these results show that although loss-offunction for WHSC1 and/or LETM1 contributes to some of the features of WHS, deletion of additional genes is required for the full expression of the phenotype, providing further support that WHS is a contiguous gene deletion disorder.

show abstract

Section: Discussionmentioning

confidence: 99%

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

et al. 2013

View full text Add to dashboard Cite

show abstract

“…These data demonstrate an intracellular residence of SK2 channels at the ER membrane of neuronal HT-22 cells, with potential importance for the CyPPA-mediated protective effects against ER stress. 13 To test this hypothesis in our model of ER stress, we applied quinine and propranolol, two known blockers of the ER membrane located K + /H + exchanger, 14 and identified significant inhibition of the protective effects of SK2 channel activation in ER stress-induced cell death (Figure 7g, Supplementary Figure S9). …”

Section: Resultsmentioning

confidence: 99%

“…14,33 On the other hand, the non-peptide SK channel blocker UCL1684 is also capable of blocking intracellularly located SK channels. 14,34 In the present study, only UCL1684 completely abolished the protective effects of CyPPA, while apamin failed to affect SK2 channels are located at the ER membrane and prevent brefeldin A-induced ER Ca 2+ depletion. To further investigate intracellular localization of SK2 channels, we co-transfected HT-22 cells with ER-targeted red fluorescence protein to visualize ER and simultaneously with green fluorescent protein (GFP)-tagged SK2 channels.…”

Section: Resultsmentioning

confidence: 99%

“…Generally, K + fluxes across the ER membrane are supposed to be important for [Ca 2+ ] ER influx and release to balance charge movements. 14,39,40 During the phase of [Ca 2+ ] ER uptake, SERCA activity is associated with an extrusion of protons. 41 Therefore, compensating mechanisms, responsible for proton re-entry, are thought to be necessary to prevent ER alkalization and enable Ca 2+ uptake by the SERCA pump, which has been shown to be inoperable with increasing pH.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Activation of SK2 channels preserves ER Ca2+ homeostasis and protects against ER stress-induced cell death

et al. 2015

View full text Add to dashboard Cite

Alteration of endoplasmic reticulum (ER) Ca2+ homeostasis leads to excessive cytosolic Ca 2+ accumulation and delayed neuronal cell death in acute and chronic neurodegenerative disorders. While our recent studies established a protective role for SK channels against excessive intracellular Ca 2+ accumulation, their functional role in the ER has not been elucidated yet. We show here that SK2 channels are present in ER membranes of neuronal HT-22 cells, and that positive pharmacological modulation of SK2 channels with CyPPA protects against cell death induced by the ER stressors brefeldin A and tunicamycin. Calcium imaging of HT-22 neurons revealed that elevated cytosolic Ca 2+ levels and decreased ER Ca 2+ load during sustained ER stress could be largely prevented by SK2 channel activation. Interestingly, SK2 channel activation reduced the amount of the unfolded protein response transcription factor ATF4, but further enhanced the induction of CHOP. Using siRNA approaches we confirmed a detrimental role for ATF4 in ER stress, whereas CHOP regulation was dispensable for both, brefeldin A toxicity and CyPPA-mediated protection. Cell death induced by blocking Ca 2+ influx into the ER with the SERCA inhibitor thapsigargin was not prevented by CyPPA. Blocking the K + efflux via K + /H + exchangers with quinine inhibited CyPPA-mediated neuroprotection, suggesting an essential role of proton uptake and K + release in the SK channel-mediated neuroprotection. Our data demonstrate that ER SK2 channel activation preserves ER Ca 2+ uptake and retention which determines cell survival in conditions where sustained ER stress contributes to progressive neuronal death.

show abstract

“…У 1965 році вийшла публікація в журналі «Human genetik», відколи особлива увага генетиків та спеціалістів інших галузей була звер-нена на дане захворювання. Після друку статті вда- Âèïàäîê ³ç ïðàêòèêè / Case Report лося виявити багато нових випадків, що дозволило детальніше вивчити клінічні особливості синдро-му Вольфа -Хіршхорна [6].…”

Section: ë³òåðàòóðíà äîâ³äêàunclassified

Досвід Діагностики Та Спостереження Дитини Із Синдромом Вольфа — Хіршхорна

Беш¹,

Matsyura²,

Bulak³

et al. 2021

View full text Add to dashboard Cite

® Нас не бачать… Нас не чують… Про нас не говорять… Думають, нас немає…Саме такі слова є стартовими на одному із сай-тів для підтримки сімей, які мають дітей-інвалідів із порушенням інтелекту. До таких захворювань належить синдром Вольфа -Хіршхорна, при яко-му життєдіяльність обмежена у зв'язку з наявними грубими фізичними вадами розвитку та глибокою розумовою відсталістю [3,8].На жаль, в Україні бракує розвинутих соціаль-них програм для підтримки дітей та їх родин із різ-ними орфанними захворюваннями. Батьки нерід-ко самостійно групуються із сім'ями, яких спіткало схоже горе. На сьогодні створені численні сайти та групи в соціальних мережах, де сім'ї підтримують одна одну, діляться досвідом щодо догляду за ді-тьми. Зокрема, на одному з іноземних інтернет-ре-сурсів написано звернення від батьків: «Читаючи медичні статті про синдром Вольфа -Хіршхорна, будь-ласка, дивіться на них з усмішкою» [2]. Ë³òåðàòóðíà äîâ³äêàСиндром одночасно документально зафіксува-ли в 1961 році німецький вчений U. Wolf та амери-канський -К. Hirschhorn [9]. Вони описали дітей із дефектами кісток лицевого черепа та цитогене-тичними підтвердженнями делеції короткого пле-ча 4-ї хромосоми. У 1965 році вийшла публікація в журналі «Human genetik», відколи особлива увага генетиків та спеціалістів інших галузей була звер-нена на дане захворювання. Після друку статті вда-

show abstract

Endoplasmic reticulum potassium–hydrogen exchanger and small conductance calcium-activated potassium channel activities are essential for ER calcium uptake in neurons and cardiomyocytes

Cited by 50 publications

References 43 publications

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

Activation of SK2 channels preserves ER Ca2+ homeostasis and protects against ER stress-induced cell death

Досвід Діагностики Та Спостереження Дитини Із Синдромом Вольфа — Хіршхорна

Contact Info

Product

Resources

About