REGULATION OF MOUSE SKELETAL-MUSCLE L-TYPE CA2-LIKE GROWTH-FACTOR-I RECEPTOR( CHANNEL BY ACTIVATION OF THE INSULIN)

We investigated the modulation of the skeletal muscle L-type Ca2+ chan nel/dihydropyridine receptor in response to insulinlike growth factor- 1 receptor (lGF-1R) activation in single extensor digitorum longus mus cle fibers from adult C57BL/6 mice. The L-type Ca2+ channel activity i n fts dual role as a voltage sensor and a selective Ca2+-conducting po re was recorded in voltage-clamp conditions. Peak Ca2+ current amplitu de 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 shi ft in 13 mV of the Ca2+ current-voltage relationship toward more negat ive potentials. The IGF-1-induced facilitation of the Ca2+ current was not associated with an effect on charge movement amplitude and/or vol tage distribution. These phenomena suggest that the L-type Ca2+ channe l structures involved in voltage sensing are not involved in the respo nse 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 b y a cAMP-dependent protein kinase inhibitor. IGf-1-dependent phosphory lation of the L-type Ca2+ channel al subunit was demonstrated by incor poration of [gamma-P-32]ATP to monolayers of adult fast-twitch skeleta l muscles. IGF-1 induced phosphorylation or a protein at the 165 kDa b and, corresponding to the L-type Ca2+ channel alpha(1) subunit. These results show that the activation of the IGF-1R facilitates skeletal mu scle L-type Ca2+ channel activity via a PKC-dependent phosphorylation mechanism.