Regulation of mouse skeletal muscle L-type Ca2+ channel by activation of the insulin-like growth factor-1 receptor.
We investigated the modulation of the skeletal muscle L-type Ca2+ channel/dihydropyridine receptor in response to insulin-like growth factor-1 receptor (IGF-1R) activation in single extensor digitorum longus muscle fibers from adult C57BL/6 mice. The L-type Ca2+ channel activity in its dual role as a voltage sensor and a selective Ca2+-conducting pore was recorded in voltage-clamp conditions. Peak Ca2+ current amplitude consistently increased after exposure to 20 ng/ml IGF-1 (EC50 = 5.6 +/- 1.8 nM). Peak IGF-1 effect on current amplitude at -20 mV was 210 +/- 18% of the control. Ca2+ current potentiation resulted from a shift in 13 mV of the Ca2+ current-voltage relationship toward more negative potentials. The IGF-1-induced facilitation of the Ca2+ current was not associated with an effect on charge movement amplitude and/or voltage distribution. These phenomena suggest that the L-type Ca2+ channel structures involved in voltage sensing are not involved in the response to the growth factor. The modulatory effect of IGF-1 on L-type Ca2+ channel was blocked by tyrosine kinase and PKC inhibitors, but not by a cAMP-dependent protein kinase inhibitor. IGF-1-dependent phosphorylation of the L-type Ca2+ channel alpha1 subunit was demonstrated by incorporation of [gamma-32P]ATP to monolayers of adult fast-twitch skeletal muscles. IGF-1 induced phosphorylation of a protein at the 165 kDa band, corresponding to the L-type Ca2+ channel alpha1 subunit. These results show that the activation of the IGF-1R facilitates skeletal muscle L-type Ca2+ channel activity via a PKC-dependent phosphorylation mechanism.
Delbono
O
O
Department of Physiology and Pharmacology, The Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157, USA.
Renganathan
M
M
Messi
M L
ML
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D018482:Muscle, Skeletal / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*
D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D007334:Insulin-Like Growth Factor I; C038806:1,4-dihydropyridine; D000255:Adenosine Triphosphate; D017526:Receptor, IGF Type 1; D011493:Protein Kinase C