title: Hypermetabolism in B-lymphocytes from malignant hyperthermia susceptible individuals.
abstract: Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle metabolism which is characterized by generalized muscle rigidity, increased body temperature, rhabdomyolysis, and severe metabolic acidosis. The underlying mechanism of MH involves excessive Ca(2+) release in myotubes via the ryanodine receptor type 1 (RyR1). As RyR1 is also expressed in B-lymphocytes, this study investigated whether cellular metabolism of native B-lymphocytes was also altered in MH susceptible (MHS) individuals. A potent activator of RyR1, 4-chloro-m-cresol (4-CmC) was used to challenge native B-lymphocytes in a real-time, metabolic assay based on a pH-sensitive silicon biosensor chip. At the cellular level, a dose-dependent, phasic acidification occurred with 4-CmC. The acidification rate, an indicator of metabolic activation, was significantly higher in B-lymphocytes from MHS patients and required 3 to 5 fold lower concentrations of 4-CmC to evoke similar acidification rates to MHN. Native B-lymphocytes from MHS individuals are more sensitive to 4-CmC than those from MHN, reflecting a greater Ca(2+) turnover. The acidification response, however, was less pronounced than in muscle cells, presumably reflecting the lower expression of RyR1 in B-lymphocytes.
authors.affiliation: Department of Anaesthesia, Intensive Care Medicine and Pain Therapy, Frankfurt University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hoppe
authors.affiliation: Division of Neurophysiology in the Center of Rare Diseases, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Hack
authors.affiliation: Division of Neurophysiology in the Center of Rare Diseases, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Lehmann-Horn
authors.affiliation: Division of Neurophysiology in the Center of Rare Diseases, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Jurkat-Rott
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove 4059, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Wearing
authors.affiliation: Department of Science and Technologies, University of Sannio, Benevento, Italy and CEINGE Advanced Biotechnologies s.c.ar.l, Naples, Italy.|Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Zullo
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Carsana
authors.affiliation: Division of Neurophysiology in the Center of Rare Diseases, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany.|Department of Neuroanaesthesiology, Neurosurgical University, Ludwig-Heilmeyerstr. 2, 89312 Guenzburg, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Klingler
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D015415:Biomarkers; D002110:Caffeine / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002461:Cell Line, Transformed; D003408:Cresols / Q000378:metabolism / Q000494:pharmacology; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D003408:Cresols; D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; C042041:3-cresol; D002118:Calcium