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Cited by 18Receptor Mechanisms and SignalingAdvanced Fluorescence Microscopy TechniquesThyroid Disorders and Treatments

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

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Fischer, Jana, Kleinau, Gunnar, Rutz, Claudia, Zwanziger, Denise, Khajavi, Noushafarin, Müller, Anne, Rehders, Maren, Brix, Klaudia +6 more·2018·Cellular and Molecular Life Sciences
DOI 10.1007/s00018-017-2728-1PMC PMC11105501
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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 G q/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.

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  • MCT8 and TSHR form a heterodimeric complex that directly modulates the selectivity of TSHR-mediated signal transduction pathways, with MCT8 profoundly reducing TSH-induced Gαq/11 signaling without affecting Gαs-mediated cAMP accumulation.

    “The two can form heterodimeric complex which directly modulates the selectivity of TSHR-mediated signal transduction pathways. MCT8 profoundly reduces the capacity of TSH to induce Gαq/11-mediated signaling at TSHR, without affecting Gαs-mediated cAMP accumulation (196).”

    From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [196]

    The Results (page not supplied) report a 60–70% reduction in the IP3 measure of Gq/11 signaling with MCT8 co-expression, while the slight reduction in TSH-induced cAMP accumulation was not statistically significant. The Discussion (page not supplied) says the TSHR/MCT8 complex *could* directly modulate pathway selectivity and leaves its exact heteromeric nature for future study; the claim presents direct modulation and a heterodimeric complex as established. (LLM, conf=0.86)

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Authors
Fischer, J., Kleinau, G., Rutz, C., Zwanziger, D., Khajavi, N., Müller, A., Rehders, M., Brix, K., Worth, C. L., Führer, D., Krude, H., Wiesner, B., Schülein, R., & Biebermann, H.
Affiliations
  • Charité – Universitätsmedizin Berlin (DE)
  • Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
  • Essen University Hospital (DE)
  • Constructor University (DE)
Corresponding author
  • Schülein, Ralf
  • Biebermann, Heike
ORCID
Venue
Cellular and Molecular Life Sciences
Publisher
Springer Science and Business Media LLC
Published
2017-12-30
Volume
75
Issue
12
Pages
2227-2239
ISSN
  • 1420-682X (ISSN-L)
  • 1420-9071
DOI
10.1007/s00018-017-2728-1
PMC
PMC11105501
OpenAlex
W2780519805
Cited by
18
References
0
Citations by year
2024: 3 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 4 · 2019: 3 · 2018: 1
FWCI
0.89
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (unspecified)
Locations
  • Cellular and Molecular Life Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
Keywords
TSH receptor, MCT8, major facilitator superfamily, biased signaling, thyroid hormone transport, thyroid follicular cells, basolateral membrane
MeSH terms
Animals, Chlorocebus aethiops, Humans, Receptors, Thyrotropin, Thyroid Gland, Signal Transduction, Gene Expression, COS Cells, Monocarboxylic Acid Transporters, Symporters, Protein Multimerization, HEK293 Cells, Protein Interaction Maps

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