Involvement of the ryanodine-sensitive Ca 2+ store in GLP-1-induced Ca 2+ oscillations in insulin-secreting HIT cells

Abstract

We investigated intracellular Ca(2+) ([Ca(2+)](i)) oscillations evoked by glucagon-like peptide 1 (GLP-1) in relation to the ryanodine receptor (RyR) and Ca(2+)-induced Ca(2+)release (CICR) mechanism in pancreatic B cell HIT. GLP-1 produced [Ca(2+)](i) oscillations in the cells, both in media with and without Ca(2+), an effect inhibited by ruthenium red and mimicked by 8-Br-cAMPS. In addition, the GLP-1-evoked [Ca(2+)](i) rise was initiated at the local intercellular peripheral cytoplasm, and a resultant expansion of the intercellular space was also observed. Caffeine induced [Ca(2+)](i) elevation in the medium with or without Ca(2+), an effect inhibited by ruthenium red. GLP-1-evoked [Ca(2+)](i) oscillations were also enhanced by IBMX, and eliminated by Rp-8-Br-cAMPS or 20 microM H-89 treatments whereas they were unaffected by 2 microM H-89 treatment. Forskolin caused a transient elevation in [Ca(2+)](i) that was reduced by Rp-8-Br-cAMPS, 2 microM or 20 microM H-89. Our results indicate that GLP-1 initially generated a local [Ca(2+)](i) elevation at the peripheral cytoplasm, subsequently producing [Ca(2+)](i) oscillations that were inhibited by ruthenium red, involving ryanodine-sensitive and cAMP-activated CICR mechanisms. The cytoplasmic levels of cAMP as well as local Ca(2+) might be responsible for [Ca(2+)](i) oscillations.

Glucagon-like peptide-1 enhances cardiac L-type Ca2+ currents via activation of the cAMP-dependent protein kinase A pathway

“…These results are along with the findings in the previous studies in rodent cardiomyocytes that GLP-1 or the GLP-1R agonist liraglutide significantly increased intracellular cAMP, which was abolished by the GLP-1R antagonist Exendin (9-39)[13,30]. Also, in the pancreatic β-cell, GLP-1 enhances cytoplasmic Ca 2+ oscillation and insulin secretion via activation of cAMP cascades[22,23]. …”

“…Elevation of intracellular Ca 2+ level can lead to an improvement of myocardial contractility. Several studies in pancreatic β-cells have shown that GLP-1 synchronizes Ca 2+ and cAMP oscillations[10,19,36] and such oscillations involves the ryanodine-sensitive Ca 2+ store[22]. In addition, the experimental evidence has shown that GLP-1 can augment Ca 2+ influx[37,38] and Ba 2+ currents[39] through L-type Ca 2+ channels via the cAMP-dependent PKA pathway in pancreatic β-cells.…”

“…Recently, a new glucagon-like peptide isolated from the intestine of the eel, Anguilla japonica [21] with a structure similar to that of oxyntomodulins has shown an inotropic effect via stimulation of Ca 2+ influx and a chronotropic effect independent of extracellular Ca 2+ . In addition, GLP-1 and glucose-dependent insulinotropic polypeptide can enhance β-cell cytoplasmic Ca 2+ oscillation and increase insulin secretion via activation of cAMP-triggered cascades[22,23]. However, the effects of GLP-1 on myocyte electrophysiology have not been carefully assessed.…”

Ca2+ signaling in prothoracicotropic hormone-stimulated prothoracic gland cells of Manduca sexta: Evidence for mobilization and entry mechanisms

“…Although the presence of a ryanodine receptor (RyR) and calciuminduced calcium release (CICR) has been postulated to promote the generation of Ca 2+ waves (Berridge, 2002); the absence of the RyR does not preclude their development (McCarron et al, 2003). Hence, it appears that Ca 2+ oscillations may arise via at least two mechanisms: (1) initiation of the process by IP 3 and perpetuation by CICR from the RyR (Sasaki et al, 2002) and (2) opening and closing of the IP 3 R as a consequence of changes in [Ca 2+ ] i between 100 and 300 nM (Bezprozvanny et al, 1991). When [Ca 2+ ] i is increased modestly , the sensitivity of the IP 3 R is increased, but at higher [Ca 2+ ] i concentrations, the IP 3 R binding site may be inhibited, thereby diminishing Ca 2+ egress from the ER, with a concomitant fall in [Ca 2+ ] i back to baseline levels (McCarron et al, 2003).…”

Regulation of cAMP dynamics by Ca2+ and G protein-coupled receptors in the pancreatic β-cell: a computational approach

“…In pancreatic ␤-cells, increased cAMP leads to increased activity of voltage-dependent calcium channels (VDCC) (26,37), decreased ATP-sensitive potassium (K ATP ) channel conductance (17,24), and increased activity of inositol 1,4,5-trisphosphate (IP 3 ) receptors in the endoplasmic reticulum contributing to calcium-induced Ca 2ϩ release (7,23,25,35), among other effects. Changes in Ca 2ϩ influx when cAMP levels are elevated can also modulate cAMP dynamics.…”