Abstract
Malignant hyperthermia (MH) is associated with abnormal regulation of intracellular calcium in skeletal muscle fibers. Cyclic adenosine diphosphate-ribose (cADPR) is an endogenous metabolite of β-NAD+ that induces Ca2+ release from intracellular stores in many tissues. Microinjection of cADPR (0.5 or 1 μM) increased the intracellular resting Ca2+ concentration ([Ca2+](i)) in intact swine skeletal muscle in a dose- dependent manner. However, the increase in [Ca2+](i) was greater in malignant-hyperthermia-susceptible (MHS) fibers than in non-susceptible (MHN) fibers. Incubation of muscle fibers in low external Ca2+ solution or in the presence of L-type Ca2+ channel entry blockers, or intracellular microinjection of heparin or ruthenium red did not modify the effect of cADPR on [Ca2+](i). Dantrolene (50 μM), a known inhibitor of intracellular Ca2+ release, decreased resting [Ca2+](i) and prevented the cADPR-induced increase in [Ca2+](i). These results provide evidence: (1) for the existence of Ca2+ release mechanisms occurring via non-ryanodine or inositol 1,4,5-trisphosphate (InsP3) receptor mechanisms; (2) that MHS skeletal muscles exhibit a higher responsiveness to cADP-ribose-induced release of Ca2+ and (3) that the ability of dantrolene to block cADP- ribose-induced release of Ca2+ could be related to its pharmacologic effect on resting [Ca2+](i).
| Original language | English (US) |
|---|---|
| Pages (from-to) | 236-242 |
| Number of pages | 7 |
| Journal | Pflugers Archiv European Journal of Physiology |
| Volume | 440 |
| Issue number | 2 |
| DOIs | |
| State | Published - 2000 |
| Externally published | Yes |
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Keywords
- Ca microelectrodes
- cADP-ribose
- Calcium
- Dantrolene
- Heparin
- Malignant hyperthermia
- Ruthenium red
- Ryanodine
- Skeletal muscle
ASJC Scopus subject areas
- Physiology
Cite this
Cyclic ADP-ribose induces a larger than normal calcium release in malignant hyperthermia-susceptible skeletal muscle fibers. / López, J. R.; Cordovez, G.; Linares, N.; Allen, P. D.
In: Pflugers Archiv European Journal of Physiology, Vol. 440, No. 2, 2000, p. 236-242.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cyclic ADP-ribose induces a larger than normal calcium release in malignant hyperthermia-susceptible skeletal muscle fibers
AU - López, J. R.
AU - Cordovez, G.
AU - Linares, N.
AU - Allen, P. D.
PY - 2000
Y1 - 2000
N2 - Malignant hyperthermia (MH) is associated with abnormal regulation of intracellular calcium in skeletal muscle fibers. Cyclic adenosine diphosphate-ribose (cADPR) is an endogenous metabolite of β-NAD+ that induces Ca2+ release from intracellular stores in many tissues. Microinjection of cADPR (0.5 or 1 μM) increased the intracellular resting Ca2+ concentration ([Ca2+](i)) in intact swine skeletal muscle in a dose- dependent manner. However, the increase in [Ca2+](i) was greater in malignant-hyperthermia-susceptible (MHS) fibers than in non-susceptible (MHN) fibers. Incubation of muscle fibers in low external Ca2+ solution or in the presence of L-type Ca2+ channel entry blockers, or intracellular microinjection of heparin or ruthenium red did not modify the effect of cADPR on [Ca2+](i). Dantrolene (50 μM), a known inhibitor of intracellular Ca2+ release, decreased resting [Ca2+](i) and prevented the cADPR-induced increase in [Ca2+](i). These results provide evidence: (1) for the existence of Ca2+ release mechanisms occurring via non-ryanodine or inositol 1,4,5-trisphosphate (InsP3) receptor mechanisms; (2) that MHS skeletal muscles exhibit a higher responsiveness to cADP-ribose-induced release of Ca2+ and (3) that the ability of dantrolene to block cADP- ribose-induced release of Ca2+ could be related to its pharmacologic effect on resting [Ca2+](i).
AB - Malignant hyperthermia (MH) is associated with abnormal regulation of intracellular calcium in skeletal muscle fibers. Cyclic adenosine diphosphate-ribose (cADPR) is an endogenous metabolite of β-NAD+ that induces Ca2+ release from intracellular stores in many tissues. Microinjection of cADPR (0.5 or 1 μM) increased the intracellular resting Ca2+ concentration ([Ca2+](i)) in intact swine skeletal muscle in a dose- dependent manner. However, the increase in [Ca2+](i) was greater in malignant-hyperthermia-susceptible (MHS) fibers than in non-susceptible (MHN) fibers. Incubation of muscle fibers in low external Ca2+ solution or in the presence of L-type Ca2+ channel entry blockers, or intracellular microinjection of heparin or ruthenium red did not modify the effect of cADPR on [Ca2+](i). Dantrolene (50 μM), a known inhibitor of intracellular Ca2+ release, decreased resting [Ca2+](i) and prevented the cADPR-induced increase in [Ca2+](i). These results provide evidence: (1) for the existence of Ca2+ release mechanisms occurring via non-ryanodine or inositol 1,4,5-trisphosphate (InsP3) receptor mechanisms; (2) that MHS skeletal muscles exhibit a higher responsiveness to cADP-ribose-induced release of Ca2+ and (3) that the ability of dantrolene to block cADP- ribose-induced release of Ca2+ could be related to its pharmacologic effect on resting [Ca2+](i).
KW - Ca microelectrodes
KW - cADP-ribose
KW - Calcium
KW - Dantrolene
KW - Heparin
KW - Malignant hyperthermia
KW - Ruthenium red
KW - Ryanodine
KW - Skeletal muscle
UR - http://www.scopus.com/inward/record.url?scp=0034130224&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034130224&partnerID=8YFLogxK
U2 - 10.1007/s004240051045
DO - 10.1007/s004240051045
M3 - Article
VL - 440
SP - 236
EP - 242
JO - Pflugers Archiv European Journal of Physiology
JF - Pflugers Archiv European Journal of Physiology
SN - 0031-6768
IS - 2
ER -