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Article

Melanocortin-4 Receptor PLC Activation Is Modulated by an Interaction with the Monocarboxylate Transporter 8

by
Larissa Anthofer
1,2,
Philipp Gmach
1,
Zeynep Cansu Uretmen Kagiali
1,
Gunnar Kleinau
3,
Jonas Rotter
2,
Robert Opitz
1,
Patrick Scheerer
3,
Annette G. Beck-Sickinger
4,
Philipp Wolf
4,
Heike Biebermann
1,
Ingo Bechmann
2,
Peter Kühnen
5,
Heiko Krude
1 and
Sarah Paisdzior
1,*
1
Institute of Experimental Pediatric Endocrinology, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, D-10117 Berlin, Germany
2
Institute of Anatomy, Leipzig University, D-04103 Leipzig, Germany
3
Group Structural Biology of Cellular Signaling, Institute of Medical Physics and Biophysics, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, D-10117 Berlin, Germany
4
Faculty of Life Sciences, Institute of Biochemistry, Leipzig University, D-04103 Leipzig, Germany
5
Department for Pediatric Endocrinology and Diabetology, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, D-10117 Berlin, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(14), 7565; https://doi.org/10.3390/ijms25147565
Submission received: 14 June 2024 / Revised: 5 July 2024 / Accepted: 6 July 2024 / Published: 10 July 2024
(This article belongs to the Special Issue G Protein-Coupled Receptor Signaling in Molecular and Cellular Physiology)
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Abstract

The melanocortin-4 receptor (MC4R) is a key player in the hypothalamic leptin–melanocortin pathway that regulates satiety and hunger. MC4R belongs to the G protein-coupled receptors (GPCRs), which are known to form heterodimers with other membrane proteins, potentially modulating receptor function or characteristics. Like MC4R, thyroid hormones (TH) are also essential for energy homeostasis control. TH transport across membranes is facilitated by the monocarboxylate transporter 8 (MCT8), which is also known to form heterodimers with GPCRs. Based on the finding in single-cell RNA-sequencing data that both proteins are simultaneously expressed in hypothalamic neurons, we investigated a putative interplay between MC4R and MCT8. We developed a novel staining protocol utilizing a fluorophore-labeled MC4R ligand and demonstrated a co-localization of MC4R and MCT8 in human brain tissue. Using in vitro assays such as BRET, IP1, and cAMP determination, we found that MCT8 modulates MC4R-mediated phospholipase C activation but not cAMP formation via a direct interaction, an effect that does not require a functional MCT8 as it was not altered by a specific MCT8 inhibitor. This suggests an extended functional spectrum of MCT8 as a GPCR signaling modulator and argues for the investigation of further GPCR-protein interactions with hitherto underrepresented physiological functions.
Keywords: protein–protein interaction; heterodimerization; MC4R; MCT8; fluorophore-labeled ligand; BRET protein–protein interaction; heterodimerization; MC4R; MCT8; fluorophore-labeled ligand; BRET

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MDPI and ACS Style

Anthofer, L.; Gmach, P.; Uretmen Kagiali, Z.C.; Kleinau, G.; Rotter, J.; Opitz, R.; Scheerer, P.; Beck-Sickinger, A.G.; Wolf, P.; Biebermann, H.; et al. Melanocortin-4 Receptor PLC Activation Is Modulated by an Interaction with the Monocarboxylate Transporter 8. Int. J. Mol. Sci. 2024, 25, 7565. https://doi.org/10.3390/ijms25147565

AMA Style

Anthofer L, Gmach P, Uretmen Kagiali ZC, Kleinau G, Rotter J, Opitz R, Scheerer P, Beck-Sickinger AG, Wolf P, Biebermann H, et al. Melanocortin-4 Receptor PLC Activation Is Modulated by an Interaction with the Monocarboxylate Transporter 8. International Journal of Molecular Sciences. 2024; 25(14):7565. https://doi.org/10.3390/ijms25147565

Chicago/Turabian Style

Anthofer, Larissa, Philipp Gmach, Zeynep Cansu Uretmen Kagiali, Gunnar Kleinau, Jonas Rotter, Robert Opitz, Patrick Scheerer, Annette G. Beck-Sickinger, Philipp Wolf, Heike Biebermann, and et al. 2024. "Melanocortin-4 Receptor PLC Activation Is Modulated by an Interaction with the Monocarboxylate Transporter 8" International Journal of Molecular Sciences 25, no. 14: 7565. https://doi.org/10.3390/ijms25147565

APA Style

Anthofer, L., Gmach, P., Uretmen Kagiali, Z. C., Kleinau, G., Rotter, J., Opitz, R., Scheerer, P., Beck-Sickinger, A. G., Wolf, P., Biebermann, H., Bechmann, I., Kühnen, P., Krude, H., & Paisdzior, S. (2024). Melanocortin-4 Receptor PLC Activation Is Modulated by an Interaction with the Monocarboxylate Transporter 8. International Journal of Molecular Sciences, 25(14), 7565. https://doi.org/10.3390/ijms25147565

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