Selective targeting of mu opioid receptors to primary cilia
Rita R. Fagan,
David F. Lee,
Matan Geron,
Grégory Scherrer,
Mark von Zastrow,
Aliza T. Ehrlich
Affiliations
Rita R. Fagan
Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94158, USA
David F. Lee
Department of Cell Biology and Physiology, UNC Neuroscience Center, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Matan Geron
Department of Cell Biology and Physiology, UNC Neuroscience Center, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Grégory Scherrer
Department of Cell Biology and Physiology, UNC Neuroscience Center, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; New York Stem Cell Foundation, Chapel Hill, NC 27599, USA
Mark von Zastrow
Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding author
Aliza T. Ehrlich
Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding author
Summary: 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.
