Li Guan Yenni H, Kieffer Brigitte L, von Zastrow Mark, Ehrlich Aliza T
bioRxiv. 2025 May 28:2025.05.28.656656. doi: 10.1101/2025.05.28.656656.
GPR88 is an orphan G protein-coupled receptor that regulates dopamine neurotransmission and is a target for neuropsychiatric disorders. In addition to the somatic membrane, GPR88 can localize to the primary cilium, a membrane microdomain known for dynamically enriching receptors and signaling molecules. However, the distribution of GPR88 in neuronal primary cilia remains uncharacterized. Here we characterize GPR88 distribution at primary cilia in two brain areas. We show that in the striatum, GPR88 localizes both to somatodendritic and primary cilia compartments on inhibitory GABAergic medium spiny neurons. In contrast, in the somatosensory cortex, GPR88 localizes to somatodendritic and nuclear compartments of excitatory spiny stellate neurons which possess primary cilia that exclude GPR88. Additionally, we found that cilia formation and length were similar between GPR88 knockout and wild-type animals. Together, we provide key evidence for neuronal cell-type specific regulation of GPR88 localization to primary cilia, suggesting neuron subtype specific regulatory mechanisms govern receptor ciliary targeting in the brain.
GPR88是一种孤儿G蛋白偶联受体，可调节多巴胺神经传递，是神经精神疾病的一个靶点。除了体细胞细胞膜外，GPR88还可定位于初级纤毛，这是一种以动态富集受体和信号分子而闻名的膜微区。然而，GPR88在神经元初级纤毛中的分布仍未得到表征。在这里，我们描述了GPR88在两个脑区初级纤毛中的分布。我们发现，在纹状体中，GPR88定位于抑制性GABA能中型多棘神经元的体树突和初级纤毛区室。相反，在躯体感觉皮层中，GPR88定位于兴奋性棘状星状神经元的体树突和核区室，这些神经元拥有排除GPR88的初级纤毛。此外，我们发现GPR88基因敲除动物和野生型动物之间的纤毛形成和长度相似。总之，我们提供了关键证据，证明GPR88定位于初级纤毛的神经元细胞类型特异性调节，表明神经元亚型特异性调节机制控制着大脑中受体的纤毛靶向。
