Journal article
Multiple Distinct Signal Pathways, Including an Autocrine Neurotrophic Mechanism, Contribute to the Survival-Promoting Effect of Depolarization on Spiral Ganglion Neurons In Vitro
The Journal of neuroscience, Vol.21(7), pp.2256-2267
04/01/2001
DOI: 10.1523/JNEUROSCI.21-07-02256.2001
PMCID: PMC6762385
PMID: 11264301
Abstract
We have shown previously that BDNF, neurotrophin-3 (NT-3), chlorphenylthio-cAMP (cpt-cAMP) (a permeant cAMP analog), and membrane depolarization promote spiral ganglion neuron (SGN) survival
in vitro
in an additive manner, depolarization having the greatest efficacy. Expression of both BDNF and of NT-3 is detectable in cultured SGNs after plating in either depolarizing or nondepolarizing medium. These neurotrophins promote survival by an autocrine mechanism; TrkB-IgG or TrkC-IgG, which block neurotrophin binding to, respectively, TrkB and TrkC, partially inhibit the trophic effect of depolarization. The mitogen-activated protein kinase kinase inhibitor PD98059 and the phosphatidylinositol-3-OH kinase inhibitor LY294002 both abolish trophic support by neurotrophins but only partially inhibit support by depolarization. Inhibition by these compounds is not additive with inhibition by Trk-IgGs. The cAMP antagonist Rp-adenosine-3′,5′-cyclic-phosphorothioate (Rp-cAMPS) abolishes survival attributable to cpt-cAMP but has no effect on that attributable to neurotrophins, nor do inhibitors of neurotrophin-dependent survival affect survival attributable to cpt-cAMP. However, Rp-cAMPS does partially inhibit depolarization-dependent survival, an inhibition that is additive with that by Trk-IgGs, PD98059, or LY294002. Moreover, Rp-cAMPS prevents depolarization-dependent survival of PC12 cells maintained in subthreshold levels of NGF. Inhibition of Ca
2+
/calmodulin-dependent protein kinases (CaMKs) with KN-62 reduces SGN survival independently of Rp-cAMPS, Trk-IgGs, and LY294002 and additively with them. Combined inhibition of Trk, cAMP, and CaMK signaling prevents depolarization-dependent survival. Thus, survival of SGNs under depolarizing conditions involves additivity among a depolarization-independent autocrine pathway, a cAMP-dependent pathway, and a CaMK-dependent pathway.
Details
- Title: Subtitle
- Multiple Distinct Signal Pathways, Including an Autocrine Neurotrophic Mechanism, Contribute to the Survival-Promoting Effect of Depolarization on Spiral Ganglion Neurons In Vitro
- Creators
- Marlan R HansenXiang-Ming ZhaJinwoong BokSteven H Green
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.21(7), pp.2256-2267
- Publisher
- Society for Neuroscience
- DOI
- 10.1523/JNEUROSCI.21-07-02256.2001
- PMID
- 11264301
- PMCID
- PMC6762385
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Language
- English
- Date published
- 04/01/2001
- Academic Unit
- Molecular Physiology and Biophysics; Biology; Neurosurgery; Otolaryngology
- Record Identifier
- 9984006420702771
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