PMID- 9334205
OWN - NLM
STAT- MEDLINE
DCOM- 19971117
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 272
IP  - 42
DP  - 1997 Oct 17
TI  - Caffeine and halothane sensitivity of intracellular Ca2+ release is altered by 15 
      calcium release channel (ryanodine receptor) mutations associated with malignant 
      hyperthermia and/or central core disease.
PG  - 26332-9
AB  - Malignant hyperthermia (MH) and central core disease (CCD) are autosomal dominant 
      disorders of skeletal muscle in which a potentially fatal hypermetabolic crisis 
      can be triggered by commonly used anesthetic agents. To date, 17 mutations in the 
      human RYR1 gene encoding the Ca2+ release channel of skeletal muscle sarcoplasmic 
      reticulum (the ryanodine receptor) have been associated with MH and/or CCD. 
      Although many of these mutations have been linked to MH and/or CCD, with high lod 
      (log of the odds favoring linkage versus nonlinkage) scores, others have been 
      found in single, small families. Independent biochemical evidence for a causal 
      role for these mutations in MH is available for only two mutants. Mutations 
      corresponding to the human MH mutations were made in a full-length rabbit RYR1 
      cDNA, and wild type and mutant cDNAs were transfected into HEK-293 cells. After 
      about 48 h, intact cells were loaded with the fluorescent Ca2+ indicator, fura-2, 
      and intracellular Ca2+ release, induced by caffeine or halothane, was measured by 
      photometry. Ca2+ release in cells expressing MH or CCD mutant ryanodine receptors 
      was invariably significantly more sensitive to low concentrations of caffeine and 
      halothane than Ca2+ release in cells expressing wild type receptors or receptors 
      mutated in other regions of the molecule. Linear regression analysis showed that 
      there is a strong correlation (r = 0.95, p < 0.001) between caffeine sensitivity 
      of different RYR1 mutants measured by the cellular Ca2+ photometry assay and by 
      the clinical in vitro caffeine halothane contracture test (IVCT). The correlation 
      was weaker, however, for halothane (r = 0.49, p > 0.05). Abnormal sensitivity in 
      the Ca2+ photometry assay provides supporting evidence for a causal role in MH 
      for each of 15 single amino acid mutations in the ryanodine receptor. The study 
      demonstrates the usefulness of the cellular Ca2+ photometry assay in the 
      assessment of the sensitivity to caffeine and halothane of specific ryanodine 
      receptor mutants.
FAU - Tong, J
AU  - Tong J
AD  - Banting and Best Department of Medical Research, University of Toronto, Charles 
      H. Best Institute, Toronto, Ontario M5G 1L6, Canada.
FAU - Oyamada, H
AU  - Oyamada H
FAU - Demaurex, N
AU  - Demaurex N
FAU - Grinstein, S
AU  - Grinstein S
FAU - McCarthy, T V
AU  - McCarthy TV
FAU - MacLennan, D H
AU  - MacLennan DH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA, Complementary)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Ryanodine Receptor Calcium Release Channel)
RN  - 3G6A5W338E (Caffeine)
RN  - SY7Q814VUP (Calcium)
RN  - UQT9G45D1P (Halothane)
SB  - IM
MH  - Animals
MH  - Caffeine/*pharmacology
MH  - Calcium/*metabolism
MH  - Cell Line
MH  - DNA, Complementary
MH  - Halothane/*pharmacology
MH  - Humans
MH  - Malignant Hyperthermia/*genetics
MH  - Mutagenesis, Site-Directed
MH  - Myopathies, Nemaline/*genetics
MH  - Rabbits
MH  - Recombinant Proteins/genetics/metabolism
MH  - Ryanodine Receptor Calcium Release Channel/drug effects/genetics/*metabolism
EDAT- 1997/10/23 00:00
MHDA- 1997/10/23 00:01
CRDT- 1997/10/23 00:00
PHST- 1997/10/23 00:00 [pubmed]
PHST- 1997/10/23 00:01 [medline]
PHST- 1997/10/23 00:00 [entrez]
AID - S0021-9258(18)66422-1 [pii]
AID - 10.1074/jbc.272.42.26332 [doi]
PST - ppublish
SO  - J Biol Chem. 1997 Oct 17;272(42):26332-9. doi: 10.1074/jbc.272.42.26332.