TRPC5 controls the adrenaline-mediated counter regulation of hypoglycemia.

Autor:	Bröker-Lai J; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany., Rego Terol J; Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Germany., Richter C; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany., Mathar I; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany., Wirth A; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany., Kopf S; Klinik für Endokrinologie, Diabetologie, Stoffwechsel und Klinische Chemie, Heidelberg, Germany.; Institute for Diabetes and Cancer, Helmholtz Diabetes Center, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany., Moreno-Pérez A; Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Germany., Büttner M; Metabolomics Core Technology Platform, Centre for Organismal Studies Heidelberg (COS Heidelberg), Heidelberg, Germany., Tan LL; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany., Makke M; Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Germany., Poschet G; Metabolomics Core Technology Platform, Centre for Organismal Studies Heidelberg (COS Heidelberg), Heidelberg, Germany., Hermann J; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany., Tsvilovskyy V; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany., Haberkorn U; Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany., Wartenberg P; Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany., Susperreguy S; Signal Transduction Laboratory, Institute of Biomedical Research (BIOMED UCA CONICET) Edificio San José, Piso 3 School of Biomedical Sciences, Pontifical Catholic University of Argentina, Buenos Aires, Argentina., Berlin M; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany., Ottenheijm R; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany., Philippaert K; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany., Wu M; Institute for Diabetes and Cancer, Helmholtz Diabetes Center, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany., Wiedemann T; Institute for Diabetes and Cancer, Helmholtz Diabetes Center, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany., Herzig S; Institute for Diabetes and Cancer, Helmholtz Diabetes Center, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany., Belkacemi A; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany., Levinson RT; Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany., Agarwal N; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany., Camacho Londoño JE; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany., Klebl B; Lead Discovery Center GmbH, Dortmund, Germany., Dinkel K; Lead Discovery Center GmbH, Dortmund, Germany., Zufall F; Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Germany., Nussbaumer P; Lead Discovery Center GmbH, Dortmund, Germany., Boehm U; Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany., Hell R; Metabolomics Core Technology Platform, Centre for Organismal Studies Heidelberg (COS Heidelberg), Heidelberg, Germany., Nawroth P; Klinik für Endokrinologie, Diabetologie, Stoffwechsel und Klinische Chemie, Heidelberg, Germany.; Deutsches Zentrum für Diabetesforschung (DZD e.V), München-Neuherberg, Germany., Birnbaumer L; Signal Transduction Laboratory, Institute of Biomedical Research (BIOMED UCA CONICET) Edificio San José, Piso 3 School of Biomedical Sciences, Pontifical Catholic University of Argentina, Buenos Aires, Argentina., Leinders-Zufall T; Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Germany., Kuner R; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany., Zorn M; Klinik für Endokrinologie, Diabetologie, Stoffwechsel und Klinische Chemie, Heidelberg, Germany., Bruns D; Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Germany., Schwarz Y; Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Germany. Yvonne.Schwarz@uks.eu., Freichel M; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany. Marc.Freichel@pharma.uni-heidelberg.de.; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany. Marc.Freichel@pharma.uni-heidelberg.de.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2024 Dec; Vol. 43 (23), pp. 5813-5836. Date of Electronic Publication: 2024 Oct 07.
DOI:	10.1038/s44318-024-00231-0
Abstrakt:	Hypoglycemia triggers autonomic and endocrine counter-regulatory responses to restore glucose homeostasis, a response that is impaired in patients with diabetes and its long-term complication hypoglycemia-associated autonomic failure (HAAF). We show that insulin-evoked hypoglycemia is severely aggravated in mice lacking the cation channel proteins TRPC1, TRPC4, TRPC5, and TRPC6, which cannot be explained by alterations in glucagon or glucocorticoid action. By using various TRPC compound knockout mouse lines, we pinpointed the failure in sympathetic counter-regulation to the lack of the TRPC5 channel subtype in adrenal chromaffin cells, which prevents proper adrenaline rise in blood plasma. Using electrophysiological analyses, we delineate a previously unknown signaling pathway in which stimulation of PAC1 or muscarinic receptors activates TRPC5 channels in a phospholipase-C-dependent manner to induce sustained adrenaline secretion as a crucial step in the sympathetic counter response to insulin-induced hypoglycemia. By comparing metabolites in the plasma, we identified reduced taurine levels after hypoglycemia induction as a commonality in TRPC5-deficient mice and HAAF patients. Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests. (© 2024. The Author(s).)
Databáze:	MEDLINE
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