Malignant hyperthermia and Alzheimer's disease causative mutations modulate calcium signaling in T lymphocytes.

Abstract

Intracellular Ca2+ channels play a pivotal role in lymphocyte Ca2+ signaling and functions, but how the mutations in these channels that cause diseases of the brain and muscle affect the T cell Ca2+ signaling are poorly understood. Gain-of-function RyR1-p.R163C mutation in ryanodine receptor 1 (RyR1) deregulates Ca2+ signaling in skeletal muscle and causes malignant hyperthermia syndrome in humans under triggering conditions. Mutations in the presenilin 1 gene have been associated with an early onset of familial Alzheimer's dementia (AD). We explored whether mutations in ryanodine receptor 1 ( RyR1-p.R163C) and presenilin 1 (PS1-dE9) genes encoding intracellular Ca2+ release channels affect Ca2+ responses in T lymphocytes.We found that T lymphocytes from heterozygous RyR1-p.R163C knock-in mutant mice (HET T cells) display measurable aberrations in resting cytosolic Ca2+ concentration ([Ca2+]i), Ca2+ release from the intracellular store, and store-operated Ca2+ entry (SOCE), compared with the WT T cells. Pretreatment of HET T cells with ryanodine receptor inhibitors ryanodine or dantrolene reduced disparities between HET and WT T cells in the resting [Ca2+]i, and the ability of thapsigargin, an inhibitor of the sarco-endoplasmic reticulum Ca2+ ATPase (SERCA), to mobilize Ca2+ from the store. Furthermore, T cells from TgF344-AD rats (TgF344-AD T cells) expressing mutant PS1-dE9 gene display enhanced SOCE elicited in the presence of SERCA activity compared with the WT T cells. Pretreatment of TgF344-AD T cells with dantrolene reduced differences in SOCE between TgF344-AD T cells and WT T cells. These findings indicate that intracellular Ca2+ release channel channelopathies associated with neurological and skeletal muscle dysfunctions may affect T cell-mediated immune responses. Whether the altered immune cell responses contribute to the pathogenesis of malignant hyperthermia and AD diseases remains to be determined. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.