ACTIVATION OF CALCIUM-DEPENDENT POTASSIUM CHANNELS IN RAT-BRAIN NEURONS BY NEUROTROPHIN-3 AND NERVE GROWTH-FACTOR

The neurotrophins are signaling factors that are essential for surviva l and differentiation of distinct neuronal populations during the deve lopment and regeneration of the nervous system. The long-term effects of neurotrophins have been studied in detail, but little is known abou t their acute effects on neuronal activity. Here we use permeabilized whole-cell patch clamp to demonstrate that neurotrophin-3 (NT-3) and n erve growth factor activate calcium-dependent, paxilline-sensitive pot assium channels (BK channels) in cortical neurons. Application of NT-3 or nerve growth factor produced a rapid and gradual rise in BK curren t that was sustained for 30-50 min; brain-derived neurotrophic factor, ciliary neurotrophic factor, and insulin-like growth factor-1 had no significant effect, The response to NT-3 was blocked by inhibitors of protein kinases, phospholipase C, and serine/threonine protein phospha tase 1 and 2a, Omission of Ca2+ from the extracellular medium prevente d the NT-3 effect. Our results indicate that NT-3 stimulates BK channe l activity in cortical neurons through a signaling pathway that involv es Trk tyrosine kinase, phospholipase C, and protein dephosphorylation and is calcium-dependent. Activation of BK channels may be a major me chanism by which neurotrophins acutely regulate neuronal activity.