Selective targeting of mu opioid receptors to primary cilia

Opioid receptors are therapeutically important G protein-coupled receptors (GPCRs) with diverse neuromodulatory effects. The functional consequences of opioid receptor activation are known to depend on receptor location in the plasma membrane, but mechanisms mediating selective localization of receptors to any particular membrane domain remain elusive. Here, we demonstrate the targeting of the mu opioid receptor (MOR) to the primary cilium, a discrete microdomain of the somatic plasma membrane, both in vivo and in cultured cells. We further show that ciliary targeting is specific to MORs, requires a 17-residue sequence unique to the MOR cytoplasmic tail, and additionally requires the Tubby-like protein 3 (TULP3) ciliary adaptor protein. Our results reveal the potential for opioid receptors to undergo selective localization to the primary cilium. We propose that ciliary targeting is mediated through an elaboration of the recycling pathway, directed by a specific C-terminal recycling sequence in cis and requiring TULP3 in trans. [Display omitted] •MOR is targeted to primary cilia in brain and cultured neurons•MOR localization to cilia requires a 17-residue sequence also involved in recycling•Ciliary targeting is unique to the MOR cytoplasmic tail as compared to DOR and KOR•MOR ciliary targeting requires the TULP3 ciliary adaptor protein The primary cilium defines a unique microdomain of the plasma membrane with restricted cargo access. Fagan et al. find that the mu-type opioid receptor (MOR) localizes to neuronal primary cilia. They demonstrate that cilia targeting requires a C-terminal recycling sequence unique to MORs and the TULP3 ciliary adaptor protein.