The importance of nerve growth factor (NGF) modulation of pancreatic beta cells is demonstrated by the fact that these cells secrete and respond to this trophic factor. Among NGF effects on beta cells is an increase in Na+ and Ca2+ current densities. This study investigates the mechanisms involved in the NGF-induced increase in Na+ current and the implications of this effect for insulin secretion. The following results were obtained in single beta cells cultured with NGF for 5-7 days: 1) A steady-state level of mRNA coding for type III sodium channel alpha subunit increased twofold compared with that for control cells. 2) The increase in Na+ current density was blocked either by cycloheximide or by actinomycin D, indicating that it is mediated by protein synthesis and mRNA transcription. 3) NGF treatment strengthened, by nearly fourfold, the beta-cell electrical activity; this effect is partially related to the increased Na+ current, because tetrodotoxin (TTX) decreased the duration of the depolarized plateau level. 4) Single beta cells secreted nearly two times more insulin in response to 5.6 or 15.6 mM glucose. This effect was inhibited by TTX, indicating that the enhanced Na+ current plays an important role. These data suggest that NGF could preserve an adequate expression of sodium channels and that impairment of NGF modulation could lead to deficient insulin secretion and diabetes mellitus.