{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T16:50:15Z","timestamp":1793033415771,"version":"4.5.0"},"reference-count":74,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T00:00:00Z","timestamp":1731628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Florida Heart Research Foundation."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Malignant hyperthermia (MH) is a genetic disorder triggered by depolarizing muscle relaxants or halogenated inhalational anesthetics in genetically predisposed individuals who have a chronic elevated intracellular Ca2+ concentration ([Ca2+]i) in their muscle cells. We have reported that the muscle dysregulation of [Ca2+]i impairs glucose uptake, leading to the development of insulin resistance in two rodent experimental models. In this study, we simultaneously measured the [Ca2+]i and glucose uptake in single enzymatically isolated hippocampal pyramidal neurons from wild-type (WT) and MH-R163C mice. The [Ca2+]i was recorded using a Ca2+-selective microelectrode, and the glucose uptake was assessed utilizing the fluorescent glucose analog 2-NBDG. The MH-R163C hippocampal neurons exhibited elevated [Ca2+]i and impaired insulin-dependent glucose uptake compared with the WT neurons. Additionally, exposure to isoflurane exacerbated these deficiencies in the MH-R163C neurons, while the WT neurons remained unaffected. Lowering [Ca2+]i using a Ca2+-free solution, SAR7334, or dantrolene increased the glucose uptake in the MH-R163C neurons without significantly affecting the WT neurons. However, further reduction of the [Ca2+]i below the physiological level using BAPTA decreased the insulin-dependent glucose uptake in both genotypes. Furthermore, the homogenates of the MH-R163C hippocampal neurons showed an altered protein expression of the PI3K\/Akt signaling pathway and GLUT4 compared with the WT mice. Our study demonstrated that the chronic elevation of [Ca2+]i was sufficient to compromise the insulin-dependent glucose uptake in the MH-R163C hippocampal neurons. Moreover, reducing the [Ca2+]i within a specific range (100\u2013130 nM) could reverse insulin resistance, a hallmark of type 2 diabetes mellitus (T2D).<\/jats:p>","DOI":"10.3390\/cells13221888","type":"journal-article","created":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T06:59:13Z","timestamp":1731653953000},"page":"1888","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Impairment of Glucose Uptake Induced by Elevated Intracellular Ca2+ in Hippocampal Neurons of Malignant Hyperthermia-Susceptible Mice"],"prefix":"10.3390","volume":"13","author":[{"given":"Arkady","family":"Uryash","sequence":"first","affiliation":[{"name":"Division of Neonatology, Mount Sinai Medical Center, Miami, FL 33140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Mijares","sequence":"additional","affiliation":[{"name":"Centro de Biof\u00edsica y Bioqu\u00edmica, Instituto Venezolano de Investigaciones Cient\u00edficas, Caracas 1020-A, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9401-2226","authenticated-orcid":false,"given":"Jose A.","family":"Adams","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Mount Sinai Medical Center, Miami, FL 33140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1211-2432","authenticated-orcid":false,"given":"Jose R.","family":"Lopez","sequence":"additional","affiliation":[{"name":"Department of Research, Mount Sinai Medical Center, Miami, FL 33140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s13023-015-0310-1","article-title":"Malignant hyperthermia: A review","volume":"10","author":"Rosenberg","year":"2015","journal-title":"Orphanet J. 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