GPR88 localization to primary cilia in neurons is cell-type specific

This is the first demonstration of cell-type specific GPCR localization to primary cilia in vivo in intact brain tissue. 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 and not primary cilia of excitatory spiny stellate neurons. In addition, we found that cilia density 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. Graphical Abstract lsa;9/2/e202503366/GA F1 GA