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Pituitary adenylate cyclase-activating polypeptide induces translocation of its G-protein-coupled receptor into caveolin-enriched membrane microdomains, leading to enhanced cyclic AMP generation and neurite outgrowth in PC12 cells
journal contribution
posted on 2007-07-11, 00:00 authored by W Zhang, Wei DuanWei Duan, Steve Cheung, Z Huang, K Shao, Q T LiPituitary adenylate cyclase-activating polypeptide (PACAP), a member of the secretin/glucagon/vasoactive intestinal peptide family expressed throughout the nervous system, binds to the PACAP-specific G-protein-coupled receptor family members to promote both neuronal differentiation and survival. Although the PACAP receptor is known to activate its effector protein, adenylate cyclase (AC), and thus enhance cAMP generation, the molecular mechanism utilized by the receptor to activate AC is lacking. Here, we show that PACAP induces neurite outgrowth in PC12 cells by induction of translocation of the PACAP type 1 receptor (PAC1R) into caveolin-enriched Triton X-100-insoluble microdomains, leading to stronger PAC1R-AC interaction and elevated cAMP production. Moreover, we demonstrate that translocation of PAC1R is blocked by various treatments that selectively disrupt caveolae. As a result, intracellular cAMP level is decreased and consequently the PACAP-induced neurite outgrowth retarded. In contrast, addition of exogenous ganglioside GM1 to the cells shows the opposite effects. These results therefore identify the PACAP-induced translocation of its G-protein-coupled receptor into caveolae, where both AC and the regulating G-proteins reside, as the key molecular event in activating AC and inducing cAMP-mediated differentiation of PC12 cells.
History
Journal
Journal of neurochemistryVolume
103Issue
3Pagination
1157 - 1167Publisher
Wiley-Blackwell Publishing LtdLocation
Chichester, EnglandPublisher DOI
ISSN
0022-3042eISSN
1471-4159Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2007, The AuthorsUsage metrics
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No categories selectedKeywords
cyclic AMPlipid rafts\/caveolaeneurite outgrowthpituitary adenylate cyclase-activating polypeptide • pituitary adenylate cyclase-activating polypeptide receptorssignal transductionScience & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyNeurosciencesNeurosciences & Neurologypituitary adenylate cyclase-activating polypeptidepituitary adenylate cyclaseactivating polypeptide receptorsNERVE GROWTH-FACTORLIPID RAFTSSIGNAL-TRANSDUCTIONANCHORED PROTEINSCOMPARTMENTATIONGANGLIOSIDESEXPRESSIONDIFFERENTIATIONCOLOCALIZATIONOVEREXPRESSION
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