Functional role of neuroendocrine-specific protein-like 1 in membrane translocation of GLUT4.
OBJECTIVE
In skeletal muscles, dantrolene inhibits the exercise-induced membrane translocation of GLUT4. It has been postulated that the inhibitory action of dantrolene on Ca(2+) release from the sarcoplasmic reticulum (SR) causes inhibition of exercise-induced glucose uptake; however, the precise mechanism has not been adequately studied.


METHODS
We discovered that dantrolene can bind to skeletal-type neuroendocrine-specific protein-like 1 (sk-NSPl1) with photoreactive dantrolene derivatives. In sk-NSPl1-deficient muscles, we examined the change in glucose uptake and the membrane translocation of GLUT4. In addition, we examined the change in blood glucose and also measured the glycogen level in both isolated and in situ skeletal muscles after electrical stimulation using our mutant mouse.


RESULTS
In sk-NSPl1-deficient muscles, exercise-induced glucose uptake was totally abolished with no change in insulin-induced glucose uptake. The Ca(2+) release mechanism and its inhibition by dantrolene were completely preserved in these muscles. The expression of GLUT4 in the mutant muscles also appeared unchanged. Confocal imaging and results using the membrane isolation method showed that exercise/contraction did not enhance GLUT4 translocation in these sk-NSPl1-deficient muscles under conditions of adequate muscle glycogen consumption. The blood glucose level in normal mice was reduced by electrical stimulation of the hind limbs, but that in mutant mice was unchanged.


CONCLUSIONS
sk-NSPl1 is a novel dantrolene receptor that plays an important role in membrane translocation of GLUT4 induced by contraction/exercise. The 23-kDa sk-NSPl1 may also be involved in the regulation of glucose levels in the whole body.
Ikemoto
Takaaki
T
Functional Probe Research Laboratory, RIKEN Center for Molecular Imaging Science, Kobe, Japan. tikemotoriko@riken.jp
Hosoya
Takamitsu
T
Takata
Kumi
K
Aoyama
Hiroshi
H
Hiramatsu
Toshiyuki
T
Onoe
Hirotaka
H
Suzuki
Masaaki
M
Endo
Makoto
M
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003620:Dantrolene / Q000031:analogs & derivatives / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018613:Microscopy, Confocal; D009119:Muscle Contraction; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010805:Physical Conditioning, Animal; D021381:Protein Transport; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D008565:Membrane Proteins; D009124:Muscle Proteins; D009125:Muscle Relaxants, Central; D009419:Nerve Tissue Proteins; D011955:Receptors, Drug; C484735:Rtn2 protein, mouse; D019788:Fluorodeoxyglucose F18; D003620:Dantrolene; D005947:Glucose; D002118:Calcium