Complex formation of skeletal muscle Ca2+-regulatory membrane proteins by halothane.
In skeletal muscle, halothane affects the functions of several Ca2+-regulatory membrane proteins involved in the excitation-contraction-relaxation cycle. To investigate the mechanism by which this volatile anesthetic interferes with Ca2+-homeostasis, we studied potential changes in protein-protein interactions by halothane. Using comparative immunoblotting of microsomal muscle proteins separated on native and denaturing gels, we show here that halothane induces oligomerization of the terminal cisternae Ca2+-binding protein calsequestrin, the junctional ryanodine receptor Ca2+-release channel and the transverse-tubular alpha1-dihydropyridine receptor. This agrees with previous reports on the modulation of Ca2+-release activity by halothane since interactions between the voltage-sensing alpha1-dihydropyridine receptor, the ryanodine receptor and the luminal Ca2+-reservoir might result in a rapid release of Ca2+-ions. Furthermore, this study supports the idea that specific protein sites are involved in the action of inhalational anesthetics and that halothane might trigger abnormal Ca2+-homeostasis in malignant hyperthermia via oligomerization of the mutated ryanodine receptor.
Froemming
G R
GR
Department of Pharmacology, National University of Ireland, University College Dublin, Belfield.
Dillane
D J
DJ
Ohlendieck
K
K
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry / Q000187:drug effects; D020746:Calcium Channels, L-Type; D002155:Calsequestrin / Q000737:chemistry / Q000187:drug effects; D019281:Dimerization; D006221:Halothane / Q000494:pharmacology*; D008565:Membrane Proteins / Q000737:chemistry / Q000187:drug effects*; D009119:Muscle Contraction / Q000187:drug effects; D009124:Muscle Proteins / Q000737:chemistry / Q000187:drug effects; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000187:drug effects