IGF-1 modulates N and L calcium channels in a PI 3-kinase-dependent manner.
Receptor tyrosine kinases (RTKs) have long been associated with proliferation in non-neural cells, although they are also expressed in postmitotic neurons. We demonstrate that insulin-like growth factor-1 (IGF-1) induces within seconds a large, tyrosine-kinase-dependent increase in calcium channel currents in cerebellar granule neurons. Separation of channel subtypes reveals that, while P, Q, and R channels are unaffected, N and L channel activities are strongly potentiated at specific membrane voltages: N currents triple at depolarized potentials, while L currents rapidly increase 4-fold at hyperpolarized potentials. Moreover, transient expression of dominant-negative and wild-type phosphatidylinositol 3-OH kinase (PI 3-kinase) subunits, as well as application of specific inhibitors, demonstrates that PI 3-kinase is an essential and rate-limiting messenger in this signaling pathway. Our results indicate that N and L calcium channels are downstream targets of neuronal RTKs and suggest that RTK modulation may control calcium-dependent processes, such as neurotransmitter release and IGF-1-dependent differentiation or survival.
Blair
L A
LA
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
Marshall
J
J
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D051381:Rats
D015220:Calcium Channels; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor)