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1.
Intracellular serotonin modulates insulin secretion from pancreatic ß-cells by protein serotonylation
Nils Paulmann, Maik Grohmann, Jörg-Peter Voigt, Bettina Bert, Jakob Vowinckel, Michael Bader, Maša Skelin, Marko Jevšek, Heidrun Fink, Marjan Rupnik, Diego Walther, 2009, izvirni znanstveni članek

Opis: 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: insulin secretion, serotonin, insulin, glucose, diabetes mellitus, guanosine triphosphatase, exocytosis, pancreas
Objavljeno: 16.06.2017; Ogledov: 71; Prenosov: 0
.pdf Polno besedilo (774,75 KB)

2.
SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of $Ca^{2+}$ oscillations in $\beta$ cell networks
Teresa Daraio, Lidija Križančić Bombek, Marko Gosak, Ismael Valladolid-Acebes, Maša Skelin, Essam Refai, Per-Olof Berggren, Kerstin Brismar, Marjan Rupnik, Christina Bark, 2017, izvirni znanstveni članek

Opis: SNAP-25 is a protein of the core SNARE complex mediating stimulus-dependent release of insulin from pancreatic $\beta$ cells. The protein exists as two alternatively spliced isoforms, SNAP-25a and SNAP-25b, differing in 9 out of 206 amino acids, yet their specific roles in pancreatic $\beta$ cells remain unclear. We explored the effect of SNAP-25b-deficiency on glucose-stimulated insulin release in islets and found increased secretion both in vivo and in vitro. However, slow photo-release of caged $Ca^{2+}$ in $\beta$ cells within pancreatic slices showed no significant differences in $Ca^{2+}$-sensitivity, amplitude or rate of exocytosis between SNAP-25b-deficient and wild-type littermates. Therefore, we next investigated if $Ca^{2+}$ handling was affected in glucose-stimulated [beta] cells using intracellular $Ca^{2+}$-imaging and found premature activation and delayed termination of [$Ca^{2+}$] i elevations. These findings were accompanied by less synchronized $Ca^{2+}$-oscillations and hence more segregated functional $\beta$ cell networks in SNAP-25b-deficient mice. Islet gross morphology and architecture were maintained in mutant mice, although sex specific compensatory changes were observed. Thus, our study proposes that SNAP-25b in pancreatic [beta] cells, except for participating in the core SNARE complex, is necessary for accurate regulation of $Ca^{2+}$-dynamics.
Ključne besede: insulin secretion, pre-diabetes
Objavljeno: 23.08.2017; Ogledov: 27; Prenosov: 0
.pdf Polno besedilo (3,80 MB)

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