2. Academic Validation
  3. TRPC5 controls the adrenaline-mediated counter regulation of hypoglycemia

TRPC5 controls the adrenaline-mediated counter regulation of hypoglycemia

  • EMBO J. 2024 Oct 7. doi: 10.1038/s44318-024-00231-0.
Jenny Bröker-Lai # 1 2,  José Rego Terol # 3,  Christin Richter # 1,  Ilka Mathar # 1 2,  Angela Wirth # 1 2,  Stefan Kopf # 4 5,  Ana Moreno-Pérez 3,  Michael Büttner 6,  Linette Liqi Tan 1,  Mazen Makke 3,  Gernot Poschet 6,  Julia Hermann 1,  Volodymyr Tsvilovskyy 1 2,  Uwe Haberkorn 7,  Philipp Wartenberg 8,  Sebastian Susperreguy 9,  Michael Berlin 1 2,  Roger Ottenheijm 1 2,  Koenraad Philippaert 1 2,  Moya Wu 5,  Tobias Wiedemann 5,  Stephan Herzig 5,  Anouar Belkacemi 1 2,  Rebecca T Levinson 10,  Nitin Agarwal 1,  Juan E Camacho Londoño 1 2,  Bert Klebl 11,  Klaus Dinkel 11,  Frank Zufall 3,  Peter Nussbaumer 11,  Ulrich Boehm 8,  Rüdiger Hell 6,  Peter Nawroth 4 12,  Lutz Birnbaumer 9,  Trese Leinders-Zufall 3,  Rohini Kuner 1,  Markus Zorn 4,  Dieter Bruns 3,  Yvonne Schwarz 13,  Marc Freichel 14 15
Affiliations

Affiliations

  • 1 Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
  • 2 DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany.
  • 3 Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Germany.
  • 4 Klinik für Endokrinologie, Diabetologie, Stoffwechsel und Klinische Chemie, Heidelberg, Germany.
  • 5 Institute for Diabetes and Cancer, Helmholtz Diabetes Center, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany.
  • 6 Metabolomics Core Technology Platform, Centre for Organismal Studies Heidelberg (COS Heidelberg), Heidelberg, Germany.
  • 7 Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.
  • 8 Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany.
  • 9 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.
  • 10 Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany.
  • 11 Lead Discovery Center GmbH, Dortmund, Germany.
  • 12 Deutsches Zentrum für Diabetesforschung (DZD e.V), München-Neuherberg, Germany.
  • 13 Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Germany. Yvonne.Schwarz@uks.eu.
  • 14 Institute of Pharmacology, Heidelberg University, Heidelberg, Germany. Marc.Freichel@pharma.uni-heidelberg.de.
  • 15 DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany. Marc.Freichel@pharma.uni-heidelberg.de.
  • # Contributed equally.
PMID: 39375537 DOI: 10.1038/s44318-024-00231-0
Abstract

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.

Keywords

Adrenaline Secretion; Calcium Signaling; Chromaffin Cells; Hypoglycemia Associated Autonomic Failure; TRPC5 Channels.

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