Nils Paulmann (Avtor), Maik Grohmann (Avtor), Jörg-Peter Voigt (Avtor), Bettina Bert (Avtor), Jakob Vowinckel (Avtor), Michael Bader (Avtor), Maša Skelin (Avtor), Marko Jevšek (Avtor), Heidrun Fink (Avtor), Marjan Rupnik (Avtor), Diego Walther (Avtor)

Povzetek

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.

Ključne besede

fiziologija človeka;inzulin;serotonin;trebušna slinavka;hormonalna aktivnost;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UM MF - Medicinska fakulteta
UDK: 612
COBISS: 63941377 Povezava se bo odprla v novem oknu
ISSN: 1544-9173
Matična publikacija: PLoS biology
Št. ogledov: 1176
Št. prenosov: 136
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: izločanje inzulina;serotonin;inzulin;glukoza;sladkorna bolezen;diabetes mellitus;gvanozin-trifosfataza;eksocitoza;pankreas;trebušna slinavka;
URN: URN:SI:UM:
Vrsta dela (COBISS): Znanstveno delo
Strani: str. [1-10], e1000229
Letnik: ǂVol. ǂ7
Zvezek: ǂiss. ǂ10
Čas izdaje: oct. 2009
DOI: 10.1371/journal.pbio.1000229
ID: 10842979