Induction of electrical excitability by NGF requires autocrine action of a CNTF-like factor.
The overlapping expression of neurotrophin and neural cytokine receptors indicates that most neuronal populations are responsive to both classes of factors, yet relatively little is known about how these two trophic signaling systems interact to regulate neuronal phenotype. We report here that one hallmark of NGF's effects on target cells, the induction of membrane electrical excitability, requires the intermediary action of a CNTF-like factor. We found that NGF's regulation of voltage-gated potassium channels, unlike its regulation of voltage-gated sodium and calcium channels, involves a CNTF-like autocrine/paracrine loop. We showed that NGF induces secretion of a soluble factor that mimics the action of exogenous CNTF in regulating voltage-gated potassium channels and that NGF's ability to regulate this potassium channel is blocked by three independent reagents that inhibit the signaling of CNTF and/or related factors. The identity of this autocrine factor does not appear to be CNTF itself. Thus, a CNTF-like autocrine/paracrine factor is both necessary and sufficient for the regulation of potassium channels by NGF and is a key determinant of the type of electrical excitability that NGF induces in target cells.
Lesser
S S
SS
Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Holmes
T M
TM
Pittman
A J
AJ
Lo
D C
DC
D000818:Animals; D020934:Ciliary Neurotrophic Factor / Q000235:genetics* / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D009414:Nerve Growth Factors / Q000502:physiology*; D009447:Neuroblastoma; D020933:Neurotrophin 3 / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D015221:Potassium Channels; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators