Akt-dependent potentiation of L channels by insulin-like growth factor-1 is required for neuronal survival.

The insulin-like growth factor-1 (IGF-1)/receptor tyrosine kinase recently has been shown to mediate neuronal survival and potentiate the activity of specific calcium channel subtypes; survival requires Akt, a serine/threonine kinase. We demonstrate here that Akt mediates the IGF-1-induced potentiation of L channel currents, but not that of N channels. Transient expression of wild-type, dominant-negative, and constitutively active forms of Akt in cerebellar granule neurons causes, respectively, no change in IGF-1/L channel potentiation, complete inhibition of potentiation, and a dramatic increase in basal L currents accompanied by the loss of ability to induce further increases. In no case is the IGF-1 potentiation of N currents affected. We additionally find that IGF-1 partially mediates granule neuron survival via L channel activity and that Akt-dependent L channel modulation is a necessary component. Interestingly, very brief exposure (1 min) to IGF-1 triggers nearly complete survival and requires L channel activity. These results strongly suggest that neuronal receptor tyrosine kinases can control long-term calcium-dependent processes via the rapid control of voltage-sensitive channels.