Evidence of G-protein-coupled receptor and substrate transporter heteromerization at a single molecule level

Cell Mol Life Sci. 2018 Jun;75(12):2227-2239. doi: 10.1007/s00018-017-2728-1. Epub 2017 Dec 30.

Abstract

G-protein-coupled receptors (GPCRs) can constitute complexes with non-GPCR integral membrane proteins, while such interaction has not been demonstrated at a single molecule level so far. We here investigated the potential interaction between the thyrotropin receptor (TSHR) and the monocarboxylate transporter 8 (MCT8), a member of the major facilitator superfamily (MFS), using fluorescence cross-correlation spectroscopy (FCCS). Both the proteins are expressed endogenously on the basolateral plasma membrane of the thyrocytes and are involved in stimulation of thyroid hormone production and release. Indeed, we demonstrate strong interaction between both the proteins which causes a suppressed activation of Gq/11 by TSH-stimulated TSHR. Thus, we provide not only evidence for a novel interaction between the TSHR and MCT8, but could also prove this interaction on a single molecule level. Moreover, this interaction forces biased signaling at the TSHR. These results are of general interest for both the GPCR and the MFS research fields.

Keywords: GPCR; MCT8; MFS transporters; Oligomerization; TSHR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Gene Expression
  • HEK293 Cells
  • Humans
  • Monocarboxylic Acid Transporters / analysis
  • Monocarboxylic Acid Transporters / genetics
  • Monocarboxylic Acid Transporters / metabolism*
  • Protein Interaction Maps*
  • Protein Multimerization
  • Receptors, Thyrotropin / analysis
  • Receptors, Thyrotropin / genetics
  • Receptors, Thyrotropin / metabolism*
  • Signal Transduction
  • Thyroid Gland / metabolism
  • Thyroid Gland / pathology

Substances

  • Monocarboxylic Acid Transporters
  • Receptors, Thyrotropin
  • SLC16A2 protein, human