The Ryanodine Receptor Calcium Channel of β-Cells

Islam, Md. Shahidul

doi:10.2337/diabetes.51.5.1299

Cited by 112 publications

(107 citation statements)

References 121 publications

(156 reference statements)

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“…Either mechanism might increase the sensitivity of Ca 2ϩ release channels to cytosolic Ca 2ϩ , thereby gating the channel from a closed to an open conformation (10). Such a mechanism of intracellular Ca 2ϩ channel modulation might complement the previously reported ability of cAMP to sensitize Ca 2ϩ release channels in a PKA-dependent manner (62)(63)(64)(65).…”

Section: Defective Stimulus-secretion Coupling In Sur1-ko Micementioning

confidence: 64%

Epac: A New cAMP-Binding Protein in Support of Glucagon-Like Peptide-1 Receptor-Mediated Signal Transduction in the Pancreatic β-Cell

2004

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Recently published studies of islet cell function reveal unexpected features of glucagon-like peptide-1 (GLP-1) receptor-mediated signal transduction in the pancreatic ␤-cell. Although GLP-1 is established to be a cAMPelevating agent, these studies demonstrate that protein kinase A (PKA) is not the only cAMP-binding protein by which GLP-1 acts. Instead, an alternative cAMP signaling mechanism has been described, one in which GLP-1 activates cAMP-binding proteins designated as cAMPregulated guanine nucleotide exchange factors (cAMPGEFs, also known as Epac). T he insulin secretagogue hormone glucagon-like peptide-1 (GLP-1) and its structurally related peptide analogs NN2211, CJC-1131, and exendin-4 are potent stimulators of the pancreatic ␤-cell GLP-1 receptor (GLP-1-R) (1-4). When administered to type 2 diabetic subjects, these peptides exert multiple antidiabetogenic effects: they stimulate insulin secretion, they lower fasting concentrations of blood glucose, and they attenuate the elevation of blood glucose concentration that is typically observed following ingestion of a meal. Such beneficial blood glucose-lowering actions of GLP-1 indicate a usefulness of the hormone as a new therapeutic agent for the treatment of diabetes. Indeed, efforts are now under way to develop synthetic analogs of GLP-1 that exhibit an optimal pharmacokinetic and pharmacodynamic spectrum of action commensurate with their use as therapeutic agents (1).Simultaneously, efforts have been directed at elucidating the molecular basis for GLP-1-R-mediated signal transduction. Previous studies demonstrate that GLP-1 activates multiple signaling pathways in the ␤-cell (Fig. 1). These pathways include protein kinase A (PKA), Ca 2ϩ / calmodulin-regulated protein kinase (CaMK), mitogenactivated protein kinases (MAPK, ERK1/2), phosphatidylinositol 3-kinase (PI-3K), protein kinase B (PKB, Akt), and atypical protein kinase C-(PKC-). In addition, evidence exists for actions of GLP-1 mediated by protein phosphatase (calcineurin) and hormone-sensitive lipase. Some of these signaling pathways are likely to play an active role in determining the effectiveness of GLP-1 as a stimulus for pancreatic insulin secretion. They may also confer trophic factor-like actions to GLP-1 that underlie its ability to stimulate ␤-cell growth, differentiation, and survival (1).Recent studies of pancreatic ␤-cell stimulus-secretion coupling reveal the existence of an alternative cAMP signal transduction pathway by which GLP-1 may exert its effects (5-12). GLP-1 is shown to stimulate cAMP production, and the action of cAMP is demonstrated to be mediated not only by PKA, but also by a newly recognized family of cAMP-binding proteins designated as cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs, also known as Epac) (13,14). Identification of Epac as an intermediary linking the GLP-1-R to the stimulation of insulin secretion has led to an appreciation that the blood glucose-lowering effect of GLP-1 might be reproduced using pharmacological agents that activate cAMP...

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Section: Defective Stimulus-secretion Coupling In Sur1-ko Micementioning

confidence: 64%

Epac: A New cAMP-Binding Protein in Support of Glucagon-Like Peptide-1 Receptor-Mediated Signal Transduction in the Pancreatic β-Cell

2004

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“…There are two main families of intracellular Ca 2＋ channels, InsP3Rs and RyRs in insulin secreting β-cells [7][8][9][10]. Among these channels, the critical properties of RyR are that cytosolic Ca 2＋ physiologically and caffeine pharmacologically can activate this channel [11]. In the current study, we determined the role of RyRs on Ca 2＋ mobilization in the INS-1 insulinoma cell line.…”

Section: Discussionmentioning

confidence: 99%

“…They are expressed abundantly in muscle cells and neurons. A critical property of RyRs is that increased cytosolic Ca 2＋ , cyclic ADP ribose, or nicotinic acid adenine dinucleotide phosphate (NAADP) can activate this channel physiologically, resulting in even greater amplification of Ca 2＋ signals elicited by Ca 2＋ entry or release [11][12][13]. Another key property of RyRs is that caffeine at millimolar concentrations can pharmacologically cause channel opening.…”

Section: Elevation Of the Intracellular Free Calcium Concentration ([Camentioning

confidence: 99%

Ca²⁺-induced Ca²⁺Release from Internal Stores in INS-1 Rat Insulinoma Cells

Choi

Cho

Kim

et al. 2011

Korean J Physiol Pharmacol

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“…However, apart from its lack of selectivity for different PDE isoforms, IBMX could have actions that are not related to PDE-inhibitory activity, for example activation of the ryanodine receptor [65] and antagonism at adenosine receptors [66]. We found that several selective PDE3 inhibitors (Org 9935, siguazodan, SK&F 94120, ICI118233) augmented glucose-induced insulin secretion from rat and human islets, whereas selective inhibitors of PDE4 and PDE1/5 did not [57,62].…”

Section: Modulation Of Glucose-induced Insulin Secretion By Pde Inhibmentioning

confidence: 98%

Cyclic nucleotide phosphodiesterases in pancreatic islets

Pyne

Furman

2003

Diabetologia

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Cyclic nucleotide phosphodiesterases (PDEs) comprise a family of enzymes (PDE1-PDE11) which hydrolyse cyclic AMP and cyclic GMP to their biologically inactive 5′ derivatives. Cyclic AMP is an important physiological amplifier of glucose-induced insulin secretion. As PDEs are the only known mechanism for inactivating cyclic nucleotides, it is important to characterise the PDEs present in the pancreatic islet beta cells. Several studies have shown pancreatic islets or beta cells to contain PDE1C, PDE3B and PDE4, with some evidence for PDE10A. Most evidence suggests that PDE3B is the most important in relation to the regulation of insulin release, although PDE1C could have a role. PDE3-selective inhibitors augment glucose-induced insulin secretion. In contrast, activation of beta-cell PDE3B could mediate the inhibitory effect of IGF-1 and leptin on insulin secretion. In vivo, although PDE3 inhibitors augment glucose-induced insulin secretion, concomitant inhibition of PDE3B in liver and adipose tissue induce insulin resistance and PDE3 inhibitors do not induce hypoglycaemia. The development of PDE3 inhibitors as anti-diabetic agents would require differentiation between PDE3B in the beta cell and that in hepatocytes and adipocytes. Through their effects in regulating beta-cell cyclic nucleotide concentrations, PDEs could modulate beta-cell growth, differentiation and survival; some work has shown that selective inhibition of PDE4 prevents diabetes in NOD mice and that selective PDE3 inhibition blocks cytokine-induced nitric oxide production in islet cells. Further work is required to understand the mechanism of regulation and role of the various PDEs in islet-cell function and to validate them as targets for drugs to treat and prevent diabetes. [Diabetologia (2003[Diabetologia ( ) 46:1179[Diabetologia ( -1189

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The Ryanodine Receptor Calcium Channel of β-Cells

Cited by 112 publications

References 121 publications

Epac: A New cAMP-Binding Protein in Support of Glucagon-Like Peptide-1 Receptor-Mediated Signal Transduction in the Pancreatic β-Cell

Epac: A New cAMP-Binding Protein in Support of Glucagon-Like Peptide-1 Receptor-Mediated Signal Transduction in the Pancreatic β-Cell

Ca²⁺-induced Ca²⁺Release from Internal Stores in INS-1 Rat Insulinoma Cells

Cyclic nucleotide phosphodiesterases in pancreatic islets

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The Ryanodine Receptor Calcium Channel of β-Cells

Cited by 112 publications

References 121 publications

Epac: A New cAMP-Binding Protein in Support of Glucagon-Like Peptide-1 Receptor-Mediated Signal Transduction in the Pancreatic β-Cell

Epac: A New cAMP-Binding Protein in Support of Glucagon-Like Peptide-1 Receptor-Mediated Signal Transduction in the Pancreatic β-Cell

Ca2+-induced Ca2+Release from Internal Stores in INS-1 Rat Insulinoma Cells

Cyclic nucleotide phosphodiesterases in pancreatic islets

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Ca²⁺-induced Ca²⁺Release from Internal Stores in INS-1 Rat Insulinoma Cells