ArticleThe Journal of biological chemistry2014
An essential role for the K+-dependent Na+/Ca2+-exchanger, NCKX4, in melanocortin-4-receptor-dependent satiety.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 50 citations in OpenAlex.
- Mice lacking β-arrestin-2 in melanocortin 4 receptor-expressing neurons show marked metabolic deficits.JCI insight · 2026Article
- The transcriptomes of hypothalamic micropunches reveal sex differences in regulatory processes across hibernation in the Arctic ground squirrel.Physiological genomics · 2025Article
- A human obesity-associated MC4R mutation with defective Gq/11α signaling leads to hyperphagia in mice.The Journal of clinical investigation · 2024Article
- Na+/Ca2+ exchange in enamel cells is dominated by the K+-dependent NCKX exchanger.The Journal of general physiology · 2024Article
- Methods for large-scale single mediator hypothesis testing: Possible choices and comparisons.Genetic epidemiology · 2023Review
- Sodium/(calcium + potassium) exchanger NCKX4 optimizes KLK4 activity in the enamel matrix microenvironment to regulate ECM modeling.Frontiers in physiology · 2023Article
- Regulation of KInternational journal of molecular sciences · 2022Review
- GAmerican journal of physiology. Endocrinology and metabolism · 2021Article
- The transcriptome-wide association search for genes and genetic variants which associate with BMI and gestational weight gain in women with type 1 diabetes.Molecular medicine (Cambridge, Mass.) · 2021Article
- Ion Channel and Structural Remodeling in Obesity-Mediated Atrial Fibrillation.Circulation. Arrhythmia and electrophysiology · 2020Article
- Association Between Obesity-Mediated Atrial Fibrillation and Therapy With Sodium Channel Blocker Antiarrhythmic Drugs.JAMA cardiology · 2020Observational
- The melanocortin pathway and control of appetite-progress and therapeutic implications.The Journal of endocrinology · 2019Review
- A Genome-Wide Analysis of the Penumbral Volume in Inbred Mice following Middle Cerebral Artery Occlusion.Scientific reports · 2019Article
- Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective.Frontiers in endocrinology · 2019Article
- The SLC transporter in nutrient and metabolic sensing, regulation, and drug development.Journal of molecular cell biology · 2019Article
- The transcriptome of the rat subfornical organ is altered in response to early postnatal overnutrition.IBRO reports · 2018Article
- Altered CaBiochimica et biophysica acta. Molecular cell research · 2018Review
- The NaeLife · 2017Article
- RNA sequencing and proteomics approaches reveal novel deficits in the cortex ofMolecular autism · 2017Article
- Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
K(+)-dependent Na(+)/Ca(2+)-exchangers are broadly expressed in various tissues, and particularly enriched in neurons of the brain. The distinct physiological roles for the different members of this Ca(2+) transporter family are, however, not well described. Here we show that gene-targeted mice lacking the K(+)-dependent Na(+)/Ca(2+)-exchanger, NCKX4 (gene slc24a4 or Nckx4), display a remarkable anorexia with severe hypophagia and weight loss. Feeding and satiety are coordinated centrally by melanocortin-4 receptors (MC4R) in neurons of the hypothalamic paraventricular nucleus (PVN). The hypophagic response of Nckx4 knock-out mice is accompanied by hyperactivation of neurons in the PVN, evidenced by high levels of c-Fos expression. The activation of PVN neurons in both fasted Nckx4 knock-out and glucose-injected wild-type animals is blocked by Ca(2+) removal and MC4R antagonists. In cultured hypothalamic neurons, melanocyte stimulating hormone induces an MC4R-dependent and sustained Ca(2+) signal, which requires phospholipase C activity and plasma membrane Ca(2+) entry. The Ca(2+) signal is enhanced in hypothalamic neurons from Nckx4 knock-out animals, and is depressed in cells in which NCKX4 is overexpressed. Finally, MC4R-dependent oxytocin expression in the PVN, a key essential step in satiety, is prevented by blocking phospholipase C activation or Ca(2+) entry. These findings highlight an essential, and to our knowledge previously unknown, role for Ca(2+) signaling in the MC4R pathway that leads to satiety, and a novel non-redundant role for NCKX4-mediated Ca(2+) extrusion in controlling MC4R signaling and feeding behavior. Together, these findings highlight a novel pathway that potentially could be exploited to develop much needed new therapeutics to tackle eating disorders and obesity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.