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Title: The plasma membrane lipid rafts/caveolae-mediated PACAP signalling in PC12 cells
Keywords: lipid rafts, caveolae, PACAP, PC12 cells,signaling, differentiation
Issue Date: 1-Apr-2008
Citation: ZHANG WEISHI (2008-04-01). The plasma membrane lipid rafts/caveolae-mediated PACAP signalling in PC12 cells. ScholarBank@NUS Repository.
Abstract: Pituitary 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. In addition, plasma membrane lipid rafts/caveolae microdomains, which are enriched in cholesterol and glycosphingolipids, mediate many intracellular signaling cascades leading to a variety of biological outcomes. The function of these microdomains in the PACAP signalling is not clear. The current study shows 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. In addition, the distribution of the downstream effector protein Rap1 which is activated upon cAMP elevation favors the detergent-insoluble fraction upon PACAP induction. Rap1 regulates the PACAP-induced neurite outgrowth through modulating the GSK3N2 activity and subsequent ERK1/2 phosphorylation. These results therefore identify the PACAP-induced translocation of its G-protein-coupled receptor and Rap1 into lipid rafts/caveolae, where both AC and the regulating G-proteins reside, as the key molecular events in activating AC and inducing cAMP-mediated differentiation of PC12 cells. In addition, PACAP-elicited Rap1 and Ras activation accounted for the sustained and transient activation of downstream ERK1/2 activation and neurite extension. ERK1/2 translocated to nucleus and activated the transcription factors CREB and Elk, which is an essential transcriptional requirement for the effective cell differentiation.
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