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SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of Ca²⁺oscillations in ? cell networks.

ABSTRACT: SNAP-25 is a protein of the core SNARE complex mediating stimulus-dependent release of insulin from pancreatic ? 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 ? 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 Ca²⁺ in ? cells within pancreatic slices showed no significant differences in Ca²⁺-sensitivity, amplitude or rate of exocytosis between SNAP-25b-deficient and wild-type littermates. Therefore, we next investigated if Ca²⁺ handling was affected in glucose-stimulated ? cells using intracellular Ca²⁺-imaging and found premature activation and delayed termination of [Ca²⁺] _i elevations. These findings were accompanied by less synchronized Ca²⁺-oscillations and hence more segregated functional ? 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 ? cells, except for participating in the core SNARE complex, is necessary for accurate regulation of Ca²⁺-dynamics.

SUBMITTER: Daraio T

PROVIDER: S-EPMC5552776 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of Ca<sup>2+</sup>oscillations in β cell networks.

Daraio Teresa T Bombek Lidija Križančić LK Gosak Marko M Valladolid-Acebes Ismael I Klemen Maša Skelin MS Refai Essam E Berggren Per-Olof PO Brismar Kerstin K Rupnik Marjan Slak MS Bark Christina C

Scientific reports 20170810 1

SNAP-25 is a protein of the core SNARE complex mediating stimulus-dependent release of insulin from pancreatic β 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 β 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<sup>2+ ...[more]

PMID: 28798351

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Project description:AimTo determine whether hyperpolarization-activated cyclic nucleotide-gated (HCN) channels impact glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) modulation of islet Ca2+ handling and insulin secretion.MethodsThe impact of liraglutide (GLP-1 analogue) on islet Ca2+ handling, HCN currents and insulin secretion was monitored with fluorescence microscopy, electrophysiology and enzyme immunoassays, respectively. Furthermore, liraglutide-mediated β-to-δ-cell cross-communication was assessed following selective ablation of either mouse islet δ or β cells.ResultsLiraglutide increased β-cell Ca2+ oscillation frequency in mouse and human islets under stimulatory glucose conditions. This was dependent in part on liraglutide activation of HCN channels, which also enhanced insulin secretion. Similarly, liraglutide activation of HCN channels also increased β-cell Ca2+ oscillation frequency in islets from rodents exposed to a diabetogenic diet. Interestingly, liraglutide accelerated Ca2+ oscillations in a majority of islet δ cells, which showed synchronized Ca2+ oscillations equivalent to β cells; therefore, we assessed if either cell type was driving this liraglutide-mediated islet Ca2+ response. Although δ-cell loss did not impact liraglutide-mediated increase in β-cell Ca2+ oscillation frequency, β-cell ablation attenuated liraglutide-facilitated acceleration of δ-cell Ca2+ oscillations.ConclusionThe data presented here show that liraglutide-induced stimulation of islet HCN channels augments Ca2+ oscillation frequency. As insulin secretion oscillates with β-cell Ca2+ , these findings have important implications for pulsatile insulin secretion that is probably enhanced by liraglutide activation of HCN channels and therapeutics that target GLP-1Rs for treating diabetes. Furthermore, these studies suggest that liraglutide as well as GLP-1-based therapies enhance δ-cell Ca2+ oscillation frequency and somatostatin secretion kinetics in a β-cell-dependent manner.

Dataset Information

SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of Ca²⁺oscillations in ? cell networks.

Publications

SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of Ca<sup>2+</sup>oscillations in β cell networks.

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Dataset Information

SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of Ca2+oscillations in ? cell networks.

Publications

SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of Ca<sup>2+</sup>oscillations in β cell networks.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of Ca²⁺oscillations in ? cell networks.