GABAB receptor promotes its own surface expression by recruiting a Rap1-dependent signaling cascade
GABAB receptor promotes its own surface expression by recruiting a Rap1-dependent signaling cascade
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DOI：
10.1242/jcs.167056
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发表时间：
2015-06
影响因子：
4
通讯作者：
Zongyong Zhang;Wenhua Zhang;Siluo Huang;Qian Sun;Yunyun Wang;Yong-jian Hu;Ninghua Sun;Yilei Zhang;Zhihua Jiang;N. Minato;J. Pin;Li Su;Jianfeng Liu
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文献类型：
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作者：
Zongyong Zhang;Wenhua Zhang;Siluo Huang;Qian Sun;Yunyun Wang;Yong-jian Hu;Ninghua Sun;Yilei Zhang;Zhihua Jiang;N. Minato;J. Pin;Li Su;Jianfeng Liu
摘要 G 蛋白偶联受体 (GPCR) 是细胞信号传导的关键参与者，其细胞表面表达受到严格调控。对于许多 GPCR，例如 β2-AR（β2-肾上腺素能受体），受体激活会导致受体表面表达下调，这种现象已被广泛表征。相比之下，其他一些 GPCR，例如 GABAB 受体，即使经过长时间的激动剂处理，在细胞表面仍保持相对稳定。然而，其根本机制尚不清楚。在这里，我们确定小 GTPase Rap1 是促进 GABAB 受体表面表达的关键调节因子。通过 Gαi/o 激动剂刺激 GABAB 受体信号，抑制 Rap1GAPII（也称为 Rap1GAP1b，Rap1GAP1 的同种型），从而激活培养的小脑颗粒神经元 (CGN) 中的 Rap1（具有 Rap1a 和 Rap1b 两种同种型）。然后，Rap1 的活性形式通过 CGN 中的物理相互作用被招募到 GABAB 受体。这种 Rap1 依赖性信号级联通过刺激受体循环来促进 GABAB 受体表面表达。我们的结果揭示了一种调节 GPCR 表面表达的新机制，也为 GABA 神经递质的缓慢、持久的抑制作用提供了潜在的解释。摘要：GABAB 受体激活诱导 Rap1 激活，通过刺激受体循环来促进其自身表面表达，从而为 GABA 的持久作用提供了潜在的解释。
ABSTRACT G-protein-coupled receptors (GPCRs) are key players in cell signaling, and their cell surface expression is tightly regulated. For many GPCRs such as β2-AR (β2-adrenergic receptor), receptor activation leads to downregulation of receptor surface expression, a phenomenon that has been extensively characterized. By contrast, some other GPCRs, such as GABAB receptor, remain relatively stable at the cell surface even after prolonged agonist treatment; however, the underlying mechanisms are unclear. Here, we identify the small GTPase Rap1 as a key regulator for promoting GABAB receptor surface expression. Agonist stimulation of GABAB receptor signals through Gαi/o to inhibit Rap1GAPII (also known as Rap1GAP1b, an isoform of Rap1GAP1), thereby activating Rap1 (which has two isoforms, Rap1a and Rap1b) in cultured cerebellar granule neurons (CGNs). The active form of Rap1 is then recruited to GABAB receptor through physical interactions in CGNs. This Rap1-dependent signaling cascade promotes GABAB receptor surface expression by stimulating receptor recycling. Our results uncover a new mechanism regulating GPCR surface expression and also provide a potential explanation for the slow, long-lasting inhibitory action of GABA neurotransmitter. Summary: GABAB receptor activation induces Rap1 activation to promote its own surface expression by stimulating receptor recycling, thereby providing a potential explanation for the long-lasting action of GABA.