Regulation of Mouse Skeletal Muscle L-Type Ca2+Channel by Activation of the Insulin-Like Growth Factor-1 Receptor

Open Access
Publisher Website
Google Scholar
Abstract
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 α1 subunit was demonstrated by incorporation of [γ-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 α1 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.