Activation of calcium-dependent potassium channels in mouse [correction of rat] brain neurons by neurotrophin-3 and nerve growth factor.
The neurotrophins are signaling factors that are essential for survival and differentiation of distinct neuronal populations during the development and regeneration of the nervous system. The long-term effects of neurotrophins have been studied in detail, but little is known about their acute effects on neuronal activity. Here we use permeabilized whole-cell patch clamp to demonstrate that neurotrophin-3 (NT-3) and nerve growth factor activate calcium-dependent, paxilline-sensitive potassium channels (BK channels) in cortical neurons. Application of NT-3 or nerve growth factor produced a rapid and gradual rise in BK current 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 phosphatase 1 and 2a. Omission of Ca2+ from the extracellular medium prevented the NT-3 effect. Our results indicate that NT-3 stimulates BK channel activity in cortical neurons through a signaling pathway that involves Trk tyrosine kinase, phospholipase C, and protein dephosphorylation and is calcium-dependent. Activation of BK channels may be a major mechanism by which neurotrophins acutely regulate neuronal activity.
Holm
N R
NR
NeuroSearch, Glostrup, Denmark.
Christophersen
P
P
Olesen
S P
SP
Gammeltoft
S
S
D000818:Animals; D001921:Brain / Q000166:cytology / Q000196:embryology; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051036:Large-Conductance Calcium-Activated Potassium Channels; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000502:physiology*; D020933:Neurotrophin 3; D019319:Okadaic Acid / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D015221:Potassium Channels / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated; D054645:Protein Phosphatase 1; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D019319:Okadaic Acid; D011505:Protein-Tyrosine Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D002118:Calcium