Non-neuronal, peripheral serotonin deficiency causes diabetes mellitus and identifies an intracellular role for serotonin in the regulation of insulin secretion

A Bhattacharjee

A Nandi

A. A Toye

B. A Ahmed

B. O Roep

Bettina Bert

C Guilluy

D. J Walther

Diego J. Walther

E Gylfe

F Bernassola

G Jaim-Etcheverry

G. I Bell

H Ishihara

H Kajio

Heidrun Fink

I Lundquist

J. E Richmond

J. U Peter

J. V Schonfeld

J. Y Xu

Jakob Vowinckel

Jörg-Peter Voigt

K Kasai

K Nonogaki

K Uvnas-Moberg

K Yaekura

L Wang

L. A Frohman

M Hamid

M Lesurtel

M Matsuda

Maik Grohmann

Marjan Rupnik

Marko Jevšek

Maša Skelin

Michael Bader

N Plengvidhya

Nils Paulmann

P Lindstrom

P. A Smith

P. J Bungay

R Ekholm

R Murphy

R Regazzi

R. M Barbosa

S Speier

S Wild

S. S Fajans

Steve O'Rahilly

T Rose

T. J Phillips

Y. M Leung

Z Yi

English

PubMed

Crossref

Intracellular Serotonin Modulates Insulin Secretion from Pancreatic β-Cells by Protein Serotonylation

While serotonin (5-HT) co-localization with insulin in granules of pancreatic ß-cells was demonstrated more than three decades ago, its physiological role in the etiology of diabetes is stili unclear. We combined biochemical and electrophysiological analyses of mice selectively deficient in peripheral tryptophan hydroxylase (Tph1-/-) and 5-HT to show that intracellular 5-HT regulates insulin secretion. We found that these mice are diabetic and have an impaired insulin secretion due to the lack of 5-HT in the pancreas. The pharmacological restoration of peripheral 5-HT levels rescued the impaired insulin secretion in vivo. These findings were further evidenced by patch clamp experiments with isolated Tph1-/- ß-cells, which clearly showed that the secretory defect is downstream of Ca2+ -signaling and can be rescued by direct intracellular application of 5-HT via the clamp pipette. In elucidating the underlying mechanism further, we demonstrate the covalent coupling of 5-HT by transglutaminases during insulin exocytosis to two key players in insulin secretion, the small GTPases Rab3a and Rab27a. This renders them constitutively active in a receptor-independent signaling mechanism we have recently termed serotonylation. Concordantly, an inhibition of such activating serotonylation in ß-cells abates insulin secretion. We also observed inactivation of serotonylated Rab3a by enhanced proteasomal degradation, which is in line with the inactivation of other serotonylated GTPases. Our results demonstrate that 5-HT regulates insulin secretion by serotonylation of GTPases within pancreatic ß-cells and suggest that intracellular 5-HT functions in various microenvironments via this mechanism in concert with the known receptor-mediated signaling

Paulmann, Nils

Grohmann, Maik

Voigt, Jörg-Peter

Bert, Bettina

Vowinckel, Jakob

Bader, Michael

Skelin, Maša

Jevšek, Marko

Fink, Heidrun

Rupnik, Marjan

Walther, Diego

Digital library of University of Maribor

Intracellular serotonin modulates insulin secretion from pancreatic ß-cells by protein serotonylation

While serotonin (5-HT) co-localization with insulin in granules of pancreatic beta-cells was demonstrated more than three decades ago, its physiological role in the etiology of diabetes is still unclear. We combined biochemical and electrophysiological analyses of mice selectively deficient in peripheral tryptophan hydroxylase (Tph1-/-) and 5-HT to show that intracellular 5-HT regulates insulin secretion. We found that these mice are diabetic and have an impaired insulin secretion due to the lack of 5-HT in the pancreas. The pharmacological restoration of peripheral 5-HT levels rescued the impaired insulin secretion in vivo. These findings were further evidenced by patch clamp experiments with isolated Tph1-/- beta-cells, which clearly showed that the secretory defect is downstream of Ca(2+)-signaling and can be rescued by direct intracellular application of 5-HT via the clamp pipette. In elucidating the underlying mechanism further, we demonstrate the covalent coupling of 5-HT by transglutaminases during insulin exocytosis to two key players in insulin secretion, the small GTPases Rab3a and Rab27a. This renders them constitutively active in a receptor-independent signaling mechanism we have recently termed serotonylation. Concordantly, an inhibition of such activating serotonylation in beta-cells abates insulin secretion. We also observed inactivation of serotonylated Rab3a by enhanced proteasomal degradation, which is in line with the inactivation of other serotonylated GTPases. Our results demonstrate that 5-HT regulates insulin secretion by serotonylation of GTPases within pancreatic beta-cells and suggest that intracellular 5-HT functions in various microenvironments via this mechanism in concert with the known receptor-mediated signaling

Masa Skelin

Marko Jevsek

Diego J Walther

Directory of Open Access Journals

PLoS Biology

Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation.

Paulmann, N.

Grohmann, M.

Voigt, J.P.

Bert, B.

Vowinckel, J.

Bader, M.

Skelin, M.

Jevsek, M.

Fink, H.

Rupnik, M.

Walther, D.J.

MDC Repository

Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation

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https://figshare.com/articles/Intracellular_Serotonin_Modulates_Insulin_Secretion_from_Pancreatic_Cells_by_Protein_Serotonylation/145842

Intracellular Serotonin Modulates Insulin Secretion from Pancreatic β-Cells by Protein Serotonylation

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Digital library of University of Maribor

Directory of Open Access Journals

MDC Repository