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Bröker-Lai, J.* ; Rego Terol, J.* ; Richter, C.* ; Mathar, I.* ; Wirth, A.* ; Kopf, S. ; Moreno-Pérez, A.* ; Büttner, M.* ; Tan, L.L.* ; Makke, M.* ; Poschet, G.* ; Hermann, J.* ; Tsvilovskyy, V.* ; Haberkorn, U.* ; Wartenberg, P.* ; Susperreguy, S.* ; Berlin, M.* ; Ottenheijm, R.* ; Philippaert, K.* ; Wu, M. ; Wiedemann, T. ; Herzig, S. ; Belkacemi, A.* ; Levinson, R.T.* ; Agarwal, N.* ; Camacho Londoño, J.E.* ; Klebl, B.* ; Dinkel, K.* ; Zufall, F.* ; Nussbaumer, P.* ; Boehm, U.* ; Hell, R.* ; Nawroth, P.P. ; Birnbaumer, L.* ; Leinders-Zufall, T.* ; Kuner, R.* ; Zorn, M.* ; Bruns, D.* ; Schwarz, Y.* ; Freichel, M.*

TRPC5 controls the adrenaline-mediated counter regulation of hypoglycemia.

EMBO J., DOI: 10.1038/s44318-024-00231-0 (2024)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Adrenaline Secretion ; Calcium Signaling ; Chromaffin Cells ; Hypoglycemia Associated Autonomic Failure ; Trpc5 Channels; Protein-coupled Receptors; Cyclase-activating Polypeptide; Chromaffin Cells; Proopiomelanocortin Neurons; Catecholamine Release; Diabetes-mellitus; Autonomic Failure; Channel; Pacap; Mechanisms
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Zeitschrift EMBO Journal, The
Verlag Wiley
Verlagsort Heidelberg, Germany
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
Förderungen DFG (German Research Foundation - Deutsche Forschungsgemeinschaft)
Saarland University