A major function of GPCRs is to inhibit presynaptic neurotransmitter release, requiring ligand-activated receptors to couple locally to effectors at terminals. The current understanding of how this is achieved is through receptor immobilization on the terminal surface. Here, we show that opioid peptide receptors, GPCRs that mediate highly sensitive presynaptic inhibition, are instead dynamic in axons. Opioid receptors diffuse rapidly throughout the axon surface and internalize after ligand-induced activation specifically at presynaptic terminals. We delineate a parallel regulated endocytic cycle for GPCRs operating at the presynapse, separately from the synaptic vesicle cycle, which clears activated receptors from the surface of terminals and locally reinserts them to maintain the diffusible surface pool. We propose an alternate strategy for achieving local control of presynaptic effectors that, opposite to using receptor immobilization and enforced proximity, is based on lateral mobility of receptors and leverages the inherent allostery of GPCR-effector coupling.

中文翻译：

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神经调节受体的离散突触前囊泡循环。

GPCR 的一个主要功能是抑制突触前神经递质释放，需要配体激活的受体在末端与效应子局部偶联。目前对这是如何实现的理解是通过终端表面上的受体固定化。在这里，我们表明阿片肽受体，即介导高度敏感的突触前抑制的 GPCR，在轴突中是动态的。阿片受体在整个轴突表面迅速扩散，并在配体诱导激活后内化，特别是在突触前末端。我们为在突触前运行的 GPCR 描绘了一个平行调节的内吞循环，与突触小泡循环分开，突触小泡循环从末端表面清除激活的受体并在局部重新插入它们以维持可扩散的表面池。