TRPC5 controls the adrenaline-mediated counter regulation of hypoglycemia

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.

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Publication Details

Journal
The EMBO Journal
Published
2024-10-07
DOI
https://doi.org/10.1038/s44318-024-00231-0
Citations
10
Primary Topic
Ion Channels and Receptors
Type
article
Field-Weighted Citation Impact
3.61

Funders

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article

TRPC5 controls the adrenaline-mediated counter regulation of hypoglycemia

Rebecca T. Levinson, Rüdiger Hell, Lutz Birnbaumer, Christin Richter et al.
10 citations
The EMBO Journal
Ion Channels and Receptors
3.61
article

TRPC5 controls the adrenaline-mediated counter regulation of hypoglycemia

Rebecca T. Levinson, Rüdiger Hell, Lutz Birnbaumer, Christin Richter, Volodymyr Tsvilovskyy, Bert Klebl, Uwe Haberkorn, Ilka Mathar, Moya Wu, Sebastián Susperreguy, Ulrich Boehm, Linette Liqi Tan, Gernot Poschet, Trese Leinders‐Zufall, Ana Moreno-Pérez, Rohini Kuner, Angela Wirth, Roger Ottenheijm, Stefan Kopf, Dieter Bruns, Michael Berlin, Koenraad Philippaert, Klaus Dinkel, Jenny Bröker‐Lai, Peter P. Nawroth, Philipp Wartenberg, Anouar Belkacemi, Tobias Wiedemann, Yvonne Schwarz, Juan E. Camacho Londoño, Stephan Herzig, Mazen Makke, Marc Freichel, Frank Zufall, Julia Hermann, Nitin Agarwal, Peter Nußbaumer, José Rego Terol, Markus Zorn, Michael Büttner
article en
10 citations

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.

The EMBO JournalVol. 43(23)
Heidelberg University (DE), University Hospital Heidelberg (DE), Center for Environmental Health (US), Pontificia Universidad Católica Argentina (AR), Helmholtz Zentrum München (DE), German Center for Infection Research (DE), Lead Discovery Center (Germany) (DE), Heidelberg Pharma (Germany) (DE), German Centre for Cardiovascular Research (DE), Endokrinologikum (DE), German Center for Diabetes Research (DE), Saarland University (DE)
Deutsches Krebsforschungszentrum, Deutsche Forschungsgemeinschaft, Universität Heidelberg, Universität des Saarlandes
Good health and well-being
Openalex Percentile: Top 6%
Ion Channels and Receptors
3.61
DOIOpen Access PDFOpenAlex
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