Abstract
Bidirectional signaling between the sarcolemmal L-type Ca2+ channel (1,4-dihydropyridine receptor [DHPR]) and the sarcoplasmic reticulum (SR) Ca2+ release channel (type 1 ryanodine receptor [RYR1]) of skeletal muscle is essential for excitation-contraction coupling (ECC) and is a well-understood prototype of conformational coupling. Mutations in either channel alter coupling fidelity and with an added pharmacologic stimulus or stress can trigger malignant hyperthermia (MH). In this study, we measured the response of wild-type (WT), heterozygous (Het), or homozygous (Horn) RYR1-R163C knock-in mouse myotubes to maintained KT depolarization. The new findings are: (a) For all there genotypes, Ca2+ transients decay during prolonged depolarization, and this decay is not a consequence of SR depletion or RYR1 inactivation. (b) The R163C mutation retards the decay rate with a rank order WT > Het > Horn, (c) The removal of external Ca2+ or the addition of Ca2+ entry blockers (nifedipine, SKF96365, and Ni2+) enhanced the rate of decay in all genotypes, (d) When Ca2+ entry is blocked, die decay rates are slower for Horn and Het than WT, indicating that the rate of inactivation of ECC is affected by the R163C mutation and is genotype dependent (WT > Het > Horn), (e) Reduced ECC inactivation in Het and Horn myotubes was shown directly using two identical K+ depolarizations separated by varying time intervals. These data suggest that conformational changes induced by the R163C MH mutation alter the retrograde signal that is sent from RYR1 to the DHPR, delaying the inactivation of the DHPR voltage sensor
| Original language | English (US) |
|---|---|
| Pages (from-to) | 619-628 |
| Number of pages | 10 |
| Journal | Journal of General Physiology |
| Volume | 135 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2010 |
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ASJC Scopus subject areas
- Physiology
Cite this
A malignant hyperthermia-inducing mutation in RYR1 (R163C) : Alterations in Ca2+ entry, release, and retrograde signaling to the DHPR. / Estève, Eric; Eltit, José M.; Bannister, Roger A.; Pessah, Isaac N; Beam, Kurt G.; Allen, Paul D.; López, José R.
In: Journal of General Physiology, Vol. 135, No. 6, 06.2010, p. 619-628.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A malignant hyperthermia-inducing mutation in RYR1 (R163C)
T2 - Alterations in Ca2+ entry, release, and retrograde signaling to the DHPR
AU - Estève, Eric
AU - Eltit, José M.
AU - Bannister, Roger A.
AU - Pessah, Isaac N
AU - Beam, Kurt G.
AU - Allen, Paul D.
AU - López, José R.
PY - 2010/6
Y1 - 2010/6
N2 - Bidirectional signaling between the sarcolemmal L-type Ca2+ channel (1,4-dihydropyridine receptor [DHPR]) and the sarcoplasmic reticulum (SR) Ca2+ release channel (type 1 ryanodine receptor [RYR1]) of skeletal muscle is essential for excitation-contraction coupling (ECC) and is a well-understood prototype of conformational coupling. Mutations in either channel alter coupling fidelity and with an added pharmacologic stimulus or stress can trigger malignant hyperthermia (MH). In this study, we measured the response of wild-type (WT), heterozygous (Het), or homozygous (Horn) RYR1-R163C knock-in mouse myotubes to maintained KT depolarization. The new findings are: (a) For all there genotypes, Ca2+ transients decay during prolonged depolarization, and this decay is not a consequence of SR depletion or RYR1 inactivation. (b) The R163C mutation retards the decay rate with a rank order WT > Het > Horn, (c) The removal of external Ca2+ or the addition of Ca2+ entry blockers (nifedipine, SKF96365, and Ni2+) enhanced the rate of decay in all genotypes, (d) When Ca2+ entry is blocked, die decay rates are slower for Horn and Het than WT, indicating that the rate of inactivation of ECC is affected by the R163C mutation and is genotype dependent (WT > Het > Horn), (e) Reduced ECC inactivation in Het and Horn myotubes was shown directly using two identical K+ depolarizations separated by varying time intervals. These data suggest that conformational changes induced by the R163C MH mutation alter the retrograde signal that is sent from RYR1 to the DHPR, delaying the inactivation of the DHPR voltage sensor
AB - Bidirectional signaling between the sarcolemmal L-type Ca2+ channel (1,4-dihydropyridine receptor [DHPR]) and the sarcoplasmic reticulum (SR) Ca2+ release channel (type 1 ryanodine receptor [RYR1]) of skeletal muscle is essential for excitation-contraction coupling (ECC) and is a well-understood prototype of conformational coupling. Mutations in either channel alter coupling fidelity and with an added pharmacologic stimulus or stress can trigger malignant hyperthermia (MH). In this study, we measured the response of wild-type (WT), heterozygous (Het), or homozygous (Horn) RYR1-R163C knock-in mouse myotubes to maintained KT depolarization. The new findings are: (a) For all there genotypes, Ca2+ transients decay during prolonged depolarization, and this decay is not a consequence of SR depletion or RYR1 inactivation. (b) The R163C mutation retards the decay rate with a rank order WT > Het > Horn, (c) The removal of external Ca2+ or the addition of Ca2+ entry blockers (nifedipine, SKF96365, and Ni2+) enhanced the rate of decay in all genotypes, (d) When Ca2+ entry is blocked, die decay rates are slower for Horn and Het than WT, indicating that the rate of inactivation of ECC is affected by the R163C mutation and is genotype dependent (WT > Het > Horn), (e) Reduced ECC inactivation in Het and Horn myotubes was shown directly using two identical K+ depolarizations separated by varying time intervals. These data suggest that conformational changes induced by the R163C MH mutation alter the retrograde signal that is sent from RYR1 to the DHPR, delaying the inactivation of the DHPR voltage sensor
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U2 - 10.1085/jgp.200910328
DO - 10.1085/jgp.200910328
M3 - Article
C2 - 20479110
AN - SCOPUS:77953066485
VL - 135
SP - 619
EP - 628
JO - Journal of General Physiology
JF - Journal of General Physiology
SN - 0022-1295
IS - 6
ER -