Transient Receptor Potential Cation Channels and Calcium Dyshomeostasis in a Mouse Model Relevant to Malignant Hyperthermia

Conclusions Muscle cells in knock-in mice expressing theRYR1-p.G2435R mutation are hypersensitive to TRPC3/6 activators. This hypersensitivity can be negated with pharmacologic agents that block TRPC3/6 activity. This reinforces the working hypothesis that transient receptor potential cation channels play a critical role in causing intracellular calcium and sodium overload in malignant hyperthermia –susceptible muscle, both at rest and during the malignant hyperthermia crisis.Editor ’s PerspectiveWhat We Already Know about This TopicThe type 1 ryanodine receptor gene (RYR1) encoding the skeletal muscle sarcoplasmic reticulum Ca2+ release channel is the primary locus for malignant hyperthermiaMuscle expressing malignant hyperthermia-RYR1 mutations has chronically elevated intracellular resting calcium and sodium concentrations that increase several-fold on exposure to halothane or isofluraneWhat This Article Tells Us That Is NewThe hypothesis that transient receptor potential cation channels play a critical role in causing intracellular calcium and sodium overload in malignant hyperthermia susceptible muscle was tested in aRYR1-p.G2435R knock-in murine model of malignant hyperthermiaSkeletal muscle of mice expressingRYR1-p.G2435R had a significantly enhanced, extracellular Ca2+-dependent response to TRPC3/6 channel activatorsThe TRPC3/6 channel activator response could be prevented by TRPC3/6 channel blockersLocal administration of TRPC channel blockers during an active ma...
Source: Anesthesiology - Category: Anesthesiology Source Type: research