Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
Department of Chemistry, University of California, Berkeley, CA 94720.
Proc Natl Acad Sci U S A. 2023 Oct 24;120(43):e2311131120. doi: 10.1073/pnas.2311131120. Epub 2023 Oct 16.
Many neurons in the central nervous system produce a single primary cilium that serves as a specialized signaling organelle. Several neuromodulatory G-protein-coupled receptors (GPCRs) localize to primary cilia in neurons, although it is not understood how GPCR signaling from the cilium impacts circuit function and behavior. We find that the vertebrate ancient long opsin A (VALopA), a G-coupled GPCR extraretinal opsin, targets to cilia of zebrafish spinal neurons. In the developing 1-d-old zebrafish, brief light activation of VALopA in neurons of the central pattern generator circuit for locomotion leads to sustained inhibition of coiling, the earliest form of locomotion. We find that a related extraretinal opsin, VALopB, is also G-coupled, but is not targeted to cilia. Light-induced activation of VALopB also suppresses coiling, but with faster kinetics. We identify the ciliary targeting domains of VALopA. Retargeting of both opsins shows that the locomotory response is prolonged and amplified when signaling occurs in the cilium. We propose that ciliary localization provides a mechanism for enhancing GPCR signaling in central neurons.
中枢神经系统中的许多神经元都产生一个单一的初级纤毛，作为一种专门的信号细胞器。虽然尚不清楚纤毛中的 G 蛋白偶联受体 (GPCR) 信号如何影响回路功能和行为，但几种神经调制 G 蛋白偶联受体 (GPCR) 都定位于神经元中的初级纤毛。我们发现脊椎动物古老长视蛋白 A（VALopA），一种 G 偶联 GPCR 视网膜外视蛋白，靶向斑马鱼脊髓神经元的纤毛。在发育中的 1 天大的斑马鱼中，短暂的光激活运动中央模式发生器回路神经元中的 VALopA 会导致卷曲的持续抑制，这是最早的运动形式。我们发现一种相关的视网膜外视蛋白 VALopB 也是 G 偶联的，但不会靶向纤毛。光诱导的 VALopB 激活也会抑制卷曲，但动力学更快。我们确定了 VALopA 的纤毛靶向结构域。两种视蛋白的重新靶向表明，当信号发生在纤毛中时，运动反应会延长和放大。我们提出，纤毛定位为中枢神经元中的 GPCR 信号提供了一种增强机制。
