A cADP-ribose antagonist does not inhibit secretagogue-, caffeine- and nitric oxide-induced Ca2+ responses in rat pancreatic β-cells

doi:10.1016/0143-4160(95)90056-X

Cell Calcium

Volume 18, Issue 5, November 1995, Pages 411-419

https://doi.org/10.1016/0143-4160(95)90056-X Get rights and content

Abstract

It is controversial whether the Ca²⁺ mobilizing agent, cADP-ribose (cADPR), is implicated in secretagogue-mediated intracellular Ca²⁺ responses of pancreatic β-cells. In this study we utilised a potent antagonist of cADPR, 8-amino-cADPR, to determine whether cADPR is involved in glucose-, acetylcholine-, caffeine- and nitric oxide-induced intracellular Ca²⁺ responses of isolated rat β-cells. The antagonist was found to be effective in the complete inhibition of cADPR-induced Ca²⁺ release from sea urchin egg microsome preparations, when used at equivalent concentrations to cADPR (between 0.1–10 μM) in the assay. Isolated β-cells were co-loaded with upto 50 μM 8-amino-cADPR, and Fura-2 or Fluo3, by the whole-cell patch technique. At this concentration, the antagonist failed to affect standard glucose- and acetylcholine-induced increases in the intracellular free Ca²⁺ ([Ca²⁺]_i) of isolated rat pancreatic β-cells, as assessed by video ratio imaging and single wavelength microfluorimetry. Applying the same methodology, the antagonist also failed to affect NO- and caffeine-induced intracellular Ca²⁺ responses of rat β-cells. These results suggest that cADPR does not appear to play a fundamental role in β-cell Ca²⁺ signalling. As a control, patch-loading with heparin (2 mg/ml) however, abolished the acetylcholine response but neither affected the NO- or caffeine-induced mobilization of intracellular Ca²⁺. These results support the involvement of the IP₃-receptor in acetylcholine-induced mobilization of intracellular Ca²⁺, but not that invoked by caffeine.

References (19)

H.C. Lee et al.
Structural determination of a cyclic metabolite of NAD+ with intracellular Ca²⁺-mobilizing activity
J. Biol. Chem.
(1989)
G.A. Rutter et al.
Ca²⁺ stores in insulin-secreting cells: lack of effect of cADP-ribose
Cell Calcium
(1994)
T. Nilsson et al.
Heparin inhibits IP₃-induced Ca-release in permeabilised pancreatic β-cells
FEBS Lett.
(1988)
M. Poenie
Alteration of intracellular Fura-2 fluorescence by viscosity: a simple correction
Cell Calcium
(1990)
J. Theler et al.
Video imaging of cytosolic Ca ²⁺ in pancreatic (3-cells stimulated by glucose, carbachol, and ATP
J. Biol. Chem.
(1992)
Q. Li et al.
A cloned rat CD38-homologous protein and its expression in pancreatic islets
Biochem. Biophys. Res. Commun.
(1994)
A. Galione et al.
Ca²⁺-induced Ca²⁺-release in sea urchin egg homogenates: modulation by cyclic ADP-ribose
Science
(1991)
K.P.M. Currie et al.
Activation of Ca²⁺-dependent currents in cultured rat dorsal root ganglion neurones by a sperm factor and cyclic ADP ribose
Mol. Biol. Cell.
(1992)
S. Takasawa et al.
Cyclic ADP-ribose in insulin secretion from pancreatic beta-cells
Science
(1993)

There are more references available in the full text version of this article.

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Roles of cADPR and NAADP in pancreatic beta cell signaling
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Citation Excerpt :
Nanomolar concentration of abscisic acid increased glucose-stimulated insulin secretion via cADPR formation in murine and human islets [20]. However, several studies failed to detect the Ca2+ mobilizing effects of cADPR in β cells [21–24]. These discrepancies may have resulted from differences in the species, cells, and methodologies used in various labs, and further investigation is needed to settle this controversy.
Since the discovery of the pyridine nucleotide metabolites Ca²⁺ mobilizing messengers cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), they have been demonstrated to function as Ca²⁺ signaling messengers in a wide range of cell types. In this review, I will briefly summarize the roles of cADPR and NAADP in the physiological process of stimulus-secretion coupling in pancreatic β cells. I am also going to outline the current breadth of knowledge regarding intracellular Ca²⁺ stores and Ca²⁺ channels targeted by cADPR and NAADP, as well as the biogenesis of these Ca²⁺ signaling messengers. I focused on receptor-mediated Ca²⁺ signaling in mediating the effects of GLP-1 and insulin in pancreatic β cells. A better grasp in the roles of these signaling messengers will assist in our understanding of Ca²⁺ signaling as well as pathophysiology.
Calcium signaling in pancreatic β-cells in health and in Type 2 diabetes
2014, Cell Calcium
Citation Excerpt :
However, the evaluation of Ca2+ release specifically through RyRs is extremely difficult and often based on the use of pharmacological agents, such as ryanodine, caffeine or dantrolene, which might exert unspecific effects [143–148]. Using such agents, conflicting results in favor [131,133,138–140,145,149–152] or against [103,144–146,153–156] functional RyRs have been reported in β-cells. Because CICR is an explosive phenomenon, it is usually detected as rapid [Ca2+]c transients characterized by sharp rising and decaying phases.
Changes in cytosolic free Ca²⁺ concentration ([Ca²⁺]_c) play a crucial role in the control of insulin secretion from the electrically excitable pancreatic β-cell. Secretion is controlled by the finely tuned balance between Ca²⁺ influx (mainly through voltage-dependent Ca²⁺ channels, but also through voltage-independent Ca²⁺ channels like store-operated channels) and efflux pathways. Changes in [Ca²⁺]_c directly affect [Ca²⁺] in various organelles including the endoplasmic reticulum (ER), mitochondria, the Golgi apparatus, secretory granules and lysosomes, as imaged using recombinant targeted probes. Because most of these organelles have specific Ca²⁺ influx and efflux pathways, they mutually influence free [Ca²⁺] in the others. In this article, we review the mechanisms of control of [Ca²⁺] in various compartments and particularly the cytosol, the endoplasmic reticulum ([Ca²⁺]_ER), acidic stores and mitochondrial matrix ([Ca²⁺]_mito), focusing chiefly on the most important physiological stimulus of β-cells, glucose. We also briefly review some alterations of β-cell Ca²⁺ homeostasis in Type 2 diabetes.
cAMP-dependent mobilization of intracellular Ca2+ stores by activation of ryanodine receptors in pancreatic β-cells: A Ca2+ signaling system stimulated by the insulinotropic hormone glucagon-like peptide-1-(7-37)
1999, Journal of Biological Chemistry
Glucagon-like peptide-1 (GLP-1) is an intestinally derived insulinotropic hormone currently under investigation for use as a novel therapeutic agent in the treatment of type 2 diabetes mellitus. In vitro studies of pancreatic islets of Langerhans demonstrated that GLP-1 interacts with specific β-cell G protein-coupled receptors, thereby facilitating insulin exocytosis by raising intracellular levels of cAMP and Ca²⁺. Here we report that the stimulatory influence of GLP-1 on Ca²⁺ signaling results, in part, from cAMP-dependent mobilization of ryanodine-sensitive Ca²⁺ stores. Studies of human, rat, and mouse β-cells demonstrate that the binding of a fluorescent derivative of ryanodine (BODIPY FL-X ryanodine) to its receptors is specific, reversible, and of high affinity. Rat islets and BTC3 insulinoma cells are shown by reverse transcriptase polymerase chain reaction analyses to express mRNA corresponding to the type 2 isoform of ryanodine receptor-intracellular Ca²⁺ release channel (RYR2). Single-cell measurements of [Ca²⁺]_i using primary cultures of rat and human β-cells indicate that GLP-1 facilitates Ca²⁺-induced Ca²⁺ release (CICR), whereby mobilization of Ca²⁺ stores is triggered by influx of Ca²⁺ through l-type Ca²⁺ channels. In these cells, GLP-1 is shown to interact with metabolism ofd-glucose to produce a fast transient increase of [Ca²⁺]_i. This effect is reproduced by 8-Br-cAMP, but is blocked by a GLP-1 receptor antagonist (exendin-(9–39)), a cAMP antagonist ((Rp)-cAMPS), anl-type Ca²⁺ channel antagonist (nimodipine), an antagonist of the sarco(endo)plasmic reticulum Ca²⁺ ATPase (thapsigargin), or by ryanodine. Characterization of the CICR mechanism by voltage clamp analysis also demonstrates a stimulation of Ca²⁺ release by caffeine. These findings provide new support for a model of β-cell signal transduction whereby GLP-1 promotes CICR by sensitizing intracellular Ca²⁺ release channels to the stimulatory influence of cytosolic Ca²⁺.
Cyclic ADP-ribose: A Novel Ca2+-mobilising second messenger
1999, Cellular Signalling
Cyclic ADP-ribose (cADPR) was discovered as a potent Ca²⁺-mobilising natural compound in sea urchin eggs. Recently, cADPR was reported to stimulate Ca²⁺ signallling in several higher eukaryotic cell systems (e.g., smooth and cardiac muscle cells, neuronal cells, adrenal chromaffin cells, macrophages, pancreatic acinar cells and T-lymphocytes). The following aspects of the role of cADPR as a Ca²⁺-mobilising second messenger are reviewed: coupling of metabolism of cADPR to stimulation of receptors in the plasma membrane, properties and pharmacology of Ca²⁺ release by cADPR and the involvement of cADPR in Ca²⁺ entry.
Signal Transduction. Regulation of Insulin Secretion by Changes in CA2+ Concentration and Action in Pancreatic β-Cells
1999, Advances in Molecular and Cell Biology
Defects in the regulation of insulin secretion from pancreatic β-cells largely contribute to the perturbations of glucose homeostasis in noninsulin-dependent diabetes (Type 2 diabetes). Under physiological conditions, the rate of insulin release is controlled by variations in the concentration of circulating nutrients and by various hormonal and neural signals. Hormones and neurotransmitters modulate β-cell function by binding to membrane receptors and activating transduction pathways essentially similar to those existing in other cell types. In contrast, glucose, the major physiological stimulus, does not bind to a receptor but must be metabolized to induce insulin secretion. The acceleration of β-cell metabolism results in the production of a number of potential second messengers that might trigger or modulate exocytosis of storage granules containing insulin. Another peculiarity of β-cells is not so much that they are electrically excitable, but that their membrane potential is controlled by metabolism. The electrical activity induced by glucose involves marked changes in the flux of many ions across the plasma membrane. One of these ions, Ca²⁺, plays a pre-eminent role in the regulation of insulin secretion. The first indication that Ca²⁺ ions are essential players in stimulus-secretion coupling in β-cells dates back to the observation that the stimulation of insulin secretion by glucose and other agents was abrogated by omission of extracellular Ca²⁺.
7-deaza-8-bromo-cyclic ADP-ribose, the first membrane-permeant, hydrolysis-resistant cyclic ADP-ribose antagonist
1997, Journal of Biological Chemistry
Cyclic ADP-ribose (cADPR) is a putative second messenger that has been demonstrated to mobilize Ca²⁺in many cell types. Its postulated role as the endogenous regulator of ryanodine-sensitive Ca²⁺ release channels has been greatly supported by the advent and use of specific cADPR receptor antagonists such as 8-NH₂-cADPR (Walseth, T. F., and Lee, H. C. (1993)Biochim. Biophys. Acta 1178, 235–242). However, investigations of the role of cADPR in physiological responses, such as fertilization, stimulus-secretion coupling, and excitation-contraction coupling, have been hindered by the susceptibility of cADPR receptor antagonists to hydrolysis and the need to introduce these molecules into cells by microinjection or patch clamp techniques. We have recently reported on the discovery of a poorly hydrolyzable analogue of cADPR, 7-deaza-cADPR (Bailey, V. C., Sethi, J. K., Fortt, S. M., Galione, A., and Potter, B. V. L. (1997) Chem. Biol. 4, 41–51) but this, like cADPR, is an agonist of ryanodine-sensitive Ca²⁺ release channels. We therefore explored the possibility of combining antagonistic activity with that of hydrolytic resistance and now report on the biological properties of the first hydrolysis-resistant cADPR receptor antagonist, 7-deaza-8-bromo-cADPR. In addition this compound has the advantage of being membrane-permeable. Together these properties make this hybrid molecule the most powerful tool to date for studying cADPR-mediated Ca²⁺ signaling in intact cells.

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Cell Calcium

Abstract

References (19)

Structural determination of a cyclic metabolite of NAD+ with intracellular Ca²⁺-mobilizing activity

J. Biol. Chem.

Ca²⁺ stores in insulin-secreting cells: lack of effect of cADP-ribose

Cell Calcium

Heparin inhibits IP₃-induced Ca-release in permeabilised pancreatic β-cells

FEBS Lett.

Alteration of intracellular Fura-2 fluorescence by viscosity: a simple correction

Cell Calcium

Video imaging of cytosolic Ca ²⁺ in pancreatic (3-cells stimulated by glucose, carbachol, and ATP

J. Biol. Chem.

A cloned rat CD38-homologous protein and its expression in pancreatic islets

Biochem. Biophys. Res. Commun.

Ca²⁺-induced Ca²⁺-release in sea urchin egg homogenates: modulation by cyclic ADP-ribose

Science

Activation of Ca²⁺-dependent currents in cultured rat dorsal root ganglion neurones by a sperm factor and cyclic ADP ribose

Mol. Biol. Cell.

Cyclic ADP-ribose in insulin secretion from pancreatic beta-cells

Science

Cited by (25)

Roles of cADPR and NAADP in pancreatic beta cell signaling

Calcium signaling in pancreatic β-cells in health and in Type 2 diabetes

cAMP-dependent mobilization of intracellular Ca<sup>2+</sup> stores by activation of ryanodine receptors in pancreatic β-cells: A Ca<sup>2+</sup> signaling system stimulated by the insulinotropic hormone glucagon-like peptide-1-(7-37)

Cyclic ADP-ribose: A Novel Ca<sup>2+</sup>-mobilising second messenger

Signal Transduction. Regulation of Insulin Secretion by Changes in CA<sup>2+</sup> Concentration and Action in Pancreatic β-Cells

7-deaza-8-bromo-cyclic ADP-ribose, the first membrane-permeant, hydrolysis-resistant cyclic ADP-ribose antagonist

A cADP-ribose antagonist does not inhibit secretagogue-, caffeine- and nitric oxide-induced Ca2+ responses in rat pancreatic β-cells

Abstract

J. Biol. Chem.

Cell Calcium

FEBS Lett.

Cell Calcium

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Ca2+-induced Ca2+-release in sea urchin egg homogenates: modulation by cyclic ADP-ribose

Science

Activation of Ca2+-dependent currents in cultured rat dorsal root ganglion neurones by a sperm factor and cyclic ADP ribose

Mol. Biol. Cell.

Cyclic ADP-ribose in insulin secretion from pancreatic beta-cells

Science

A cADP-ribose antagonist does not inhibit secretagogue-, caffeine- and nitric oxide-induced Ca²⁺ responses in rat pancreatic β-cells

Ca²⁺-induced Ca²⁺-release in sea urchin egg homogenates: modulation by cyclic ADP-ribose

Activation of Ca²⁺-dependent currents in cultured rat dorsal root ganglion neurones by a sperm factor and cyclic ADP ribose