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Article

Label-Free Investigations on the G Protein Dependent Signaling Pathways of Histamine Receptors

1
Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany
2
Department of Pharmacological Sciences, Tohoku University, Sendai 980-8578, Japan
*
Authors to whom correspondence should be addressed.
Academic Editor: Paul Chazot
Int. J. Mol. Sci. 2021, 22(18), 9739; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189739
Received: 12 August 2021 / Revised: 3 September 2021 / Accepted: 6 September 2021 / Published: 9 September 2021
(This article belongs to the Special Issue Molecular Biology of Histamine Systems)
G protein activation represents an early key event in the complex GPCR signal transduction process and is usually studied by label-dependent methods targeting specific molecular events. However, the constrained environment of such “invasive” techniques could interfere with biological processes. Although histamine receptors (HRs) represent (evolving) drug targets, their signal transduction is not fully understood. To address this issue, we established a non-invasive dynamic mass redistribution (DMR) assay for the human H1–4Rs expressed in HEK cells, showing excellent signal-to-background ratios above 100 for histamine (HIS) and higher than 24 for inverse agonists with pEC50 values consistent with literature. Taking advantage of the integrative nature of the DMR assay, the involvement of endogenous Gαq/11, Gαs, Gα12/13 and Gβγ proteins was explored, pursuing a two-pronged approach, namely that of classical pharmacology (G protein modulators) and that of molecular biology (Gα knock-out HEK cells). We showed that signal transduction of hH1–4Rs occurred mainly, but not exclusively, via their canonical Gα proteins. For example, in addition to Gαi/o, the Gαq/11 protein was proven to contribute to the DMR response of hH3,4Rs. Moreover, the Gα12/13 was identified to be involved in the hH2R mediated signaling pathway. These results are considered as a basis for future investigations on the (patho)physiological role and the pharmacological potential of H1–4Rs. View Full-Text
Keywords: label-free; dynamic mass redistribution (DMR); G protein coupled receptors (GPCRs); histamine receptors; signaling pathways; G protein inhibitors; G protein knock-out label-free; dynamic mass redistribution (DMR); G protein coupled receptors (GPCRs); histamine receptors; signaling pathways; G protein inhibitors; G protein knock-out
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MDPI and ACS Style

Seibel-Ehlert, U.; Plank, N.; Inoue, A.; Bernhardt, G.; Strasser, A. Label-Free Investigations on the G Protein Dependent Signaling Pathways of Histamine Receptors. Int. J. Mol. Sci. 2021, 22, 9739. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189739

AMA Style

Seibel-Ehlert U, Plank N, Inoue A, Bernhardt G, Strasser A. Label-Free Investigations on the G Protein Dependent Signaling Pathways of Histamine Receptors. International Journal of Molecular Sciences. 2021; 22(18):9739. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189739

Chicago/Turabian Style

Seibel-Ehlert, Ulla, Nicole Plank, Asuka Inoue, Guenther Bernhardt, and Andrea Strasser. 2021. "Label-Free Investigations on the G Protein Dependent Signaling Pathways of Histamine Receptors" International Journal of Molecular Sciences 22, no. 18: 9739. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189739

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