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首页> 外文期刊>Journal of Neurochemistry: Offical Journal of the International Society for Neurochemistry >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.
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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.

机译：垂体腺苷酸环化酶激活多肽诱导其G蛋白偶联受体易位到富含小窝蛋白的膜微区中，从而导致PC12细胞中环状AMP的生成和神经突向外生长。

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摘要

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. 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.
机译：垂体腺苷酸环化酶激活多肽（PACAP）是在整个神经系统表达的促胰液素/胰高血糖素/血管活性肠肽家族的成员，它与PACAP特异性G蛋白偶联受体家族成员结合，从而促进神经元分化和存活。尽管已知PACAP受体会激活其效应蛋白腺苷酸环化酶（AC），从而增强cAMP的产生，但尚缺乏该受体用来激活AC的分子机制。在这里，我们显示，PACAP通过诱导PACAP 1型受体（PAC1R）进入富含卡托弗林的Triton X-100不溶微域的易位，在PC12细胞中诱导神经突向外生长，从而导致更强的PAC1R-AC相互作用和cAMP产生增加。此外，我们证明了PAC1R的易位受到选择性破坏小窝的各种治疗的阻断。结果，细胞内cAMP水平降低，并因此抑制了PACAP诱导的神经突向外生长。相反，向细胞中添加外源神经节苷脂GM1则显示相反的效果。因此，这些结果确定了PACAP诱导的其G蛋白偶联受体向小窝的迁移，其中AC和调节性G蛋白都驻留在其中，这是激活AC和诱导cAMP介导的PC12细胞分化的关键分子事件。

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