Aberrations in T cell calcium signaling and mitochondrial function predict the presence of the gain-of-function mutation in the ryanodine receptor type 1

Abstract

Gain-of-function RyR1-p.R163C mutation in ryanodine receptors type 1 (RyR1) deregulates Ca2+ signaling in skeletal muscle and causes malignant hyperthermia in humans under triggering conditions. 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 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, to mobilize Ca2+ from the store.