Arg615Cys Substitution in Pig Skeletal Ryanodine Receptors Increases Activation of Single Channels by a Segment of the Skeletal DHPR II-III Loop

Autor: Angela F. Dulhunty, Esther M. Gallant, Suzanne M. Curtis, Suzy M. Pace
Rok vydání: 2001
Předmět:
medicine.medical_specialty
Time Factors
Calcium Channels
L-Type
Protein Conformation
Swine
Lipid Bilayers
Molecular Sequence Data
Biophysics
chemistry.chemical_element
Calcium
Arginine
Ion Channels
03 medical and health sciences
0302 clinical medicine
Internal medicine
medicine
Animals
Point Mutation
Amino Acid Sequence
Cysteine
Muscle
Skeletal
Ion channel
030304 developmental biology
Calcium metabolism
0303 health sciences
Dose-Response Relationship
Drug
Voltage-dependent calcium channel
Chemistry
Ryanodine receptor
Endoplasmic reticulum
Malignant hyperthermia
Skeletal muscle
Ryanodine Receptor Calcium Release Channel
musculoskeletal system
medicine.disease
Electrophysiology
medicine.anatomical_structure
Endocrinology
Mutation
cardiovascular system
Peptides
tissues
030217 neurology & neurosurgery
Research Article
Zdroj: Biophysical Journal. 80(4):1769-1782
ISSN: 0006-3495
DOI: 10.1016/s0006-3495(01)76147-4
Popis: The effect of peptides, corresponding to sequences in the skeletal muscle dihydropyridine receptor II-III loop, on Ca(2+) release from sarcoplasmic reticulum (SR) and on ryanodine receptor (RyR) calcium release channels have been compared in preparations from normal and malignant hyperthermia (MH)-susceptible pigs. Peptide A (Thr(671)-Leu(690); 36 microM) enhanced the rate of Ca(2+) release from normal SR (SR(N)) and from SR of MH-susceptible muscle (SR(MH)) by 10 +/- 3.2 nmole/mg/min and 76 +/- 9.7 nmole/mg/min, respectively. Ca (2+) release from SR(N) or SR(MH) was not increased by control peptide NB (Gly(689)-Lys(708)). AS (scrambled A sequence; 36 microM) did not alter Ca (2+) release from SR(N), but increased release from SR(MH) by 29 +/- 4.9 nmoles/mg/min. RyR channels from MH-susceptible muscle (RyR(MH)) were up to about fourfold more strongly activated by peptide A (> or =1 nM) than normal RyR channels (RyR(N)) at -40 mV. Neither NB or AS activated RyR(N). RyR(MH) showed an approximately 1.8-fold increase in mean current with 30 microM AS. Inhibition at +40 mV was stronger in RyR(MH) and seen with peptide A (> or = 0.6 microM) and AS (> or = 0.6 microM), but not NB. These results show that the Arg(615)Cys substitution in RyR(MH) has multiple effects on RyRs. We speculate that enhanced DHPR activation of RyRs may contribute to increased Ca(2+) release from SR in MH-susceptible muscle.
Databáze: OpenAIRE
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