HTR6 and SSTR3 ciliary targeting relies on both IC3 loops and C-terminal tails

• DOI: 10.26508/lsa.202000746
• Publication Date: 2020-12-28T16:45:27Z
• Authors: Pablo Barbeito; Yuki Tachibana; Raquel Martin-Mor...; Paula Moreno; Kirk Mykytyn; Tetsuo Kobayashi; Francesc R Garcia...
• Keywords: 0301 basic medicine; Cell Membrane; Intracellular Signaling Peptides and Proteins; Transfection; 3. Good health; Mice; Protein Transport; 03 medical and health sciences; HEK293 Cells; Gene Knockdown Techniques; Receptors, Serotonin; Animals; Humans; Protein Interaction Domains and Motifs; Amino Acid Sequence; Cilia; Receptors, Somatostatin; Research Articles; Signal Transduction

G protein-coupled receptors (GPCRs) are the most common pharmacological target in human clinical practice. To perform their functions, many GPCRs must accumulate inside primary cilia, microtubule-based plasma membrane protrusions working as cellular antennae. Nevertheless, molecular mechanisms underlying GPCR ciliary targeting remain poorly understood. Serotonin receptor 6 (HTR6) and somatostatin 3 (SSTR3) two brain-enriched involved cognition pathologies such Alzheimer's disease cancer. Although third intracellular loops (IC3) of HTR6 SSTR3 suffice to non-ciliary these IC3s dispensable for themselves, suggesting contain additional sequences (CTSs). Herein, we discover characterize novel CTSs C-terminal tails (CT). These CT-CTSs (CTS2) act redundantly with IC3-CTSs (CTS1), each being sufficient targeting. In HTR6, RKQ LPG motifs critical CTS1 CTS2 function, respectively, whereas roles mostly fulfilled by AP[AS]CQ IC3 juxtamembrane residues CT. Furthermore, shed light on how promote modulating binding trafficking adapters TULP3 RABL2.