Impairment of Glucose Uptake Induced by Elevated Intracellular Ca<sup>2+</sup> in Hippocampal Neurons of Malignant Hyperthermia-Susceptible Mice
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 Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i&l...
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2024-11-01
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| author | Arkady Uryash Alfredo Mijares Jose A. Adams Jose R. Lopez |
| author_facet | Arkady Uryash Alfredo Mijares Jose A. Adams Jose R. Lopez |
| author_sort | Arkady Uryash |
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| description | 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 Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>) in their muscle cells. We have reported that the muscle dysregulation of [Ca<sup>2+</sup>]<sub>i</sub> impairs glucose uptake, leading to the development of insulin resistance in two rodent experimental models. In this study, we simultaneously measured the [Ca<sup>2+</sup>]<sub>i</sub> and glucose uptake in single enzymatically isolated hippocampal pyramidal neurons from wild-type (WT) and MH-R163C mice. The [Ca<sup>2+</sup>]<sub>i</sub> was recorded using a Ca<sup>2+</sup>-selective microelectrode, and the glucose uptake was assessed utilizing the fluorescent glucose analog 2-NBDG. The MH-R163C hippocampal neurons exhibited elevated [Ca<sup>2+</sup>]<sub>i</sub> 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 [Ca<sup>2+</sup>]<sub>i</sub> using a Ca<sup>2+</sup>-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 [Ca<sup>2+</sup>]<sub>i</sub> 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 [Ca<sup>2+</sup>]<sub>i</sub> was sufficient to compromise the insulin-dependent glucose uptake in the MH-R163C hippocampal neurons. Moreover, reducing the [Ca<sup>2+</sup>]<sub>i</sub> within a specific range (100–130 nM) could reverse insulin resistance, a hallmark of type 2 diabetes mellitus (T2D). |
| format | Article |
| id | doaj-art-006c40c06ec04ec2815dca196b82af31 |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2024-11-01 |
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| spelling | doaj-art-006c40c06ec04ec2815dca196b82af312024-11-26T17:56:58ZengMDPI AGCells2073-44092024-11-011322188810.3390/cells13221888Impairment of Glucose Uptake Induced by Elevated Intracellular Ca<sup>2+</sup> in Hippocampal Neurons of Malignant Hyperthermia-Susceptible MiceArkady Uryash0Alfredo Mijares1Jose A. Adams2Jose R. Lopez3Division of Neonatology, Mount Sinai Medical Center, Miami, FL 33140, USACentro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas 1020-A, VenezuelaDivision of Neonatology, Mount Sinai Medical Center, Miami, FL 33140, USADepartment of Research, Mount Sinai Medical Center, Miami, FL 33140, USAMalignant 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 Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>) in their muscle cells. We have reported that the muscle dysregulation of [Ca<sup>2+</sup>]<sub>i</sub> impairs glucose uptake, leading to the development of insulin resistance in two rodent experimental models. In this study, we simultaneously measured the [Ca<sup>2+</sup>]<sub>i</sub> and glucose uptake in single enzymatically isolated hippocampal pyramidal neurons from wild-type (WT) and MH-R163C mice. The [Ca<sup>2+</sup>]<sub>i</sub> was recorded using a Ca<sup>2+</sup>-selective microelectrode, and the glucose uptake was assessed utilizing the fluorescent glucose analog 2-NBDG. The MH-R163C hippocampal neurons exhibited elevated [Ca<sup>2+</sup>]<sub>i</sub> 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 [Ca<sup>2+</sup>]<sub>i</sub> using a Ca<sup>2+</sup>-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 [Ca<sup>2+</sup>]<sub>i</sub> 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 [Ca<sup>2+</sup>]<sub>i</sub> was sufficient to compromise the insulin-dependent glucose uptake in the MH-R163C hippocampal neurons. Moreover, reducing the [Ca<sup>2+</sup>]<sub>i</sub> within a specific range (100–130 nM) could reverse insulin resistance, a hallmark of type 2 diabetes mellitus (T2D).https://www.mdpi.com/2073-4409/13/22/1888intracellular Ca<sup>2+</sup>glucosehippocampal neuronsinsulin resistancedantroleneSAR7334 |
| spellingShingle | Arkady Uryash Alfredo Mijares Jose A. Adams Jose R. Lopez Impairment of Glucose Uptake Induced by Elevated Intracellular Ca<sup>2+</sup> in Hippocampal Neurons of Malignant Hyperthermia-Susceptible Mice Cells intracellular Ca<sup>2+</sup> glucose hippocampal neurons insulin resistance dantrolene SAR7334 |
| title | Impairment of Glucose Uptake Induced by Elevated Intracellular Ca<sup>2+</sup> in Hippocampal Neurons of Malignant Hyperthermia-Susceptible Mice |
| title_full | Impairment of Glucose Uptake Induced by Elevated Intracellular Ca<sup>2+</sup> in Hippocampal Neurons of Malignant Hyperthermia-Susceptible Mice |
| title_fullStr | Impairment of Glucose Uptake Induced by Elevated Intracellular Ca<sup>2+</sup> in Hippocampal Neurons of Malignant Hyperthermia-Susceptible Mice |
| title_full_unstemmed | Impairment of Glucose Uptake Induced by Elevated Intracellular Ca<sup>2+</sup> in Hippocampal Neurons of Malignant Hyperthermia-Susceptible Mice |
| title_short | Impairment of Glucose Uptake Induced by Elevated Intracellular Ca<sup>2+</sup> in Hippocampal Neurons of Malignant Hyperthermia-Susceptible Mice |
| title_sort | impairment of glucose uptake induced by elevated intracellular ca sup 2 sup in hippocampal neurons of malignant hyperthermia susceptible mice |
| topic | intracellular Ca<sup>2+</sup> glucose hippocampal neurons insulin resistance dantrolene SAR7334 |
| url | https://www.mdpi.com/2073-4409/13/22/1888 |
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