The human L-type calcium channel Cav1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes

Reinbothe, Thomas; Alkayyali, Sami; Ahlqvist, Emma; Tuomi, Tiinamaija; Isomaa, Bo; Lyssenko, Valeriya; Renström, Erik

doi:10.1007/s00125-012-2758-z

Cited by 79 publications

(60 citation statements)

References 54 publications

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“…In addition, the increase in [Ca 2+ ] i acts as a stimulus for CICR from the ER through ryanodine receptors (RyRs). ER-released Ca 2+ is an agonist of the inositol 1,4,5-triphosphate receptor (IP3R) and stimulates additional Ca 2+ release from IP3R-regulated Ca 2+ stores; RyR-and IP3R-mediated Ca 2+ release is facilitated by the PKA signaling pathway (3,47). As a result, increases in insulin biosynthesis and exocytosis cause enhanced insulin secretion, and the PKA and Epac signaling pathways serve different roles in the process of GSIS.…”

Section: Discussionmentioning

confidence: 99%

“…Thus far, the Ca 2+ channels known to be on the cell surface membranes of β-cells include voltage-dependent Ca 2+ channels (VDCCs), including Cav1.2 and Cav1.3, the Ca 2+ release-activated channel (CRAC) and transient receptor potential (TRP) family channels. A previous study revealed that Cav1.3 is associated with the regulation of insulin secretion in β-cells (3). The CRAC channel on the cell surface membrane of β-cells is activated by the release of Ca 2+ from the ER; this channel replenishes the ER with Ca 2+ , and mediates ER-regulated membrane potential and insulin secretion (4).…”

Section: +mentioning

confidence: 99%

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Glucagon‑like peptide‑1 potentiates glucose‑stimulated insulin secretion via the transient receptor potential melastatin 2 channel

Pang

Kim

et al. 2017

Exp Ther Med

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Abstract. The transient receptor potential melastatin 2 (TRPM2) channel, a Ca 2+ permeable channel activated by cAMP, is expressed on pancreatic β-cells and is responsible for the regulation of insulin secretion. It is known that glucose-stimulated insulin secretion (GSIS) can be potentiated by glucagon like peptide-1 (GLP-1), and that the changes in the extracellular glucose concentration alter the levels of intracellular adenosine ATP and cAMP. The present study hypothesized that TRPM2 mediates the modulatory effect of GLP-1 on insulin secretion. The results demonstrated that silencing of TRPM2 eliminated GLP-1-enhanced insulin secretion, indicating the involvement of TRPM2 in this process. In addition, the results of current recordings of TRPM2 and measurement of the resulting insulin secretion in β-cells in the presence of GLP-1 and various concentrations of glucose suggest that GLP-1 regulates GSIS via the TRPM2 channel. Furthermore, inhibiting the activity or expression of TRPM2 attenuated GLP-1-induced GSIS. By using specific activators or inhibitors, the present study demonstrated that the two primary downstream effectors of the GLP-1 receptor, exchange protein directly activated by cAMP and protein kinase A, differentially influence GSIS and GLP-1-potentiated GSIS. In conclusion, the present study revealed the role of TRPM2 in GLP-1-regulated insulin secretion. The results of the present study provide a novel avenue for the prevention and treatment of diabetes and its complications. IntroductionPancreatic β-cells secrete insulin via insulin-containing granules that translocate from the intracellular insulin reservoir to the cell surface membrane, fuse with the membrane and secrete insulin through exocytosis (1,2 , and mediates ER-regulated membrane potential and insulin secretion (4). TRP family channels are non-selective cation channels in general, however some members are selective with with differential permeability to Ca 2+ (5). There are ~30 types of TRP channels that have been reported to be expressed on β-cells, including TRP vanilloid, TRP ankyrin, TRP canonical and TRP melastatin (TRPM) (6). Among these channels, TRPM2, a Ca 2+ -permeable channel, was demonstrated to be associated with glucose metabolism and insulin secretion, yet little is known about the underlying mechanisms of these associations (7).In recent years, glucagon like peptide 1 (GLP-1) and its analogues, also known as incretins, have attracted much attention for their anti-diabetic properties. A previous study demonstrated that incretins are secreted following a meal and promote insulin secretion, thereby minimizing the fluctuation of postprandial blood glucose concentrations (8). However, the 'incretin effect' in patients with type 2 diabetes

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Section: Discussionmentioning

confidence: 99%

Section: +mentioning

confidence: 99%

Glucagon‑like peptide‑1 potentiates glucose‑stimulated insulin secretion via the transient receptor potential melastatin 2 channel

Pang

Kim

et al. 2017

Exp Ther Med

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“…For example, human betacell expression of CACNA1D mRNA exceeds CACNA1C mRNA by 60 times (Reinbothe et al, 2013). Although the same predominance of Cav1.3 is observed in the rat, in the mouse, Cav1.2 channels are dominant (Hiriart and AguilarBryan, 2008;Rorsman et al, 2012).…”

Section: Downloaded Frommentioning

confidence: 92%

“…This effect could impair insulin exocytosis, because release-competent granules may not be exposed to exocytotic local levels of Ca 21 (Rorsman et al, 2012). Furthermore, two single-nucleotide polymorphisms in the CACNA1D gene (Cav1.3) reduce its mRNA expression, impair insulin secretion, and are associated with type 2 diabetes (Reinbothe et al, 2013). Finally, blocking L-type calcium channels with diazoxide could inhibit hyperglycemia-induced beta-cell apoptosis .…”

Section: The Role Of Cav Channels In the Pathophysiology Of Ms And T2dmmentioning

confidence: 99%

Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

et al. 2016

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Pancreatic beta cells, unique cells that secrete insulin in response to an increase in glucose levels, play a significant role in glucose homeostasis. Glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells has been extensively explored. In this mechanism, glucose enters the cells and subsequently the metabolic cycle. During this process, the ATP/ADP ratio increases, leading to ATP-sensitive potassium (K ATP ) channel closure, which initiates depolarization that is also dependent on the activity of TRP nonselective ion channels. Depolarization leads to the opening of voltage-gated Na 1 channels (Nav) and subsequently voltage-dependent Ca 21 channels (Cav).The increase in intracellular Ca 21 triggers the exocytosis of insulin-containing vesicles. Thus, electrical activity of pancreatic beta cells plays a central role in GSIS. Moreover, many growth factors, incretins, neurotransmitters, and hormones can modulate GSIS, and the channels that participate in GSIS are highly regulated. In this review, we focus on the principal ionic channels (K ATP , Nav, and Cav channels) involved in GSIS and how classic and new proteins, hormones, and drugs regulate it. Moreover, we also discuss advances on how metabolic disorders such as metabolic syndrome and diabetes mellitus change channel activity leading to changes in insulin secretion.

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“…Our mutant mouse expresses only SNAP-25a, and thus those excitable cells that normally express SNAP-25b in the exocytosis process are affected (23,25,26,59). In this respect, it is intriguing that several genes identified in GWAS or in functional studies as carrying a risk for susceptibility for T2D encode proteins that are important for insulin secretion from β cells, including potassium channels, voltage-gated Ca 2+ channels, and G protein-coupled receptors (34)(35)(36)(37)(38). These genes also are expressed in other excitable cells, including neurons, and therefore it is possible to envisage a scenario similar to that of our SNAP-25b-deficient mice in which a small imbalance in stimulus-dependent exocytosis mechanisms in excitable cells deregulates the interplay of metabolic signals and is followed by obesity and T2D.…”

Section: (E and F) Hypothalamic Pstat3 Is Decreased In All Experimentmentioning

confidence: 99%

Replacing SNAP-25b with SNAP-25a expression results in metabolic disease

Valladolid‐Acebes

Daraio

Brismar

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Synaptosomal-associated protein of 25 kDa (SNAP-25) is a key molecule in the soluble N-ethylmaleimide-sensitive factor attachment protein (SNARE) complex mediating fast Ca 2+ -triggered release of hormones and neurotransmitters, and both splice variants, SNAP-25a and SNAP-25b, can participate in this process. Here we explore the hypothesis that minor alterations in the machinery mediating regulated membrane fusion can increase the susceptibility for metabolic disease and precede obesity and type 2 diabetes. Thus, we used a mouse mutant engineered to express normal levels of SNAP-25 but only SNAP-25a. These SNAP-25b-deficient mice were exposed to either a control or a high-fat/high-sucrose diet. Monitoring of food intake, body weight, hypothalamic function, and lipid and glucose homeostases showed that SNAP-25b-deficient mice fed with control diet developed hyperglycemia, liver steatosis, and adipocyte hypertrophy, conditions dramatically exacerbated when combined with the high-fat/high-sucrose diet. Thus, modified SNARE function regulating stimulus-dependent exocytosis can increase the vulnerability to and even provoke metabolic disease. When combined with a high-fat/high-sucrose diet, this vulnerability resulted in diabesity. Our SNAP-25b-deficient mouse may represent a diabesity model.O n-going lifestyle changes, including oversized meals with excessive amounts of sugar and fat, have led to a worldwide pandemic of obesity and type 2 diabetes (T2D) (1). These diseases and their comorbidities cause individual suffering and represent a heavy financial burden on society (2, 3). The term "diabesity" is used to define the coincidence of obesity with T2D under conditions of exaggerated intake of energy-dense diets (4-6). Moreover, genomewide association studies (GWAS) have identified polymorphisms associated with obesity and T2D, indicating that genetic factors predispose certain individuals to diabesity (7-11).Signs of metabolic diseases include impaired regulated release of hormones, particularly insulin as in T2D (4, 12). Likewise, the secretion of inflammatory markers and other peripheral bioactive peptides is either increased (e.g., leptin, resistin, and adipsin) or decreased (e.g., ghrelin and adiponectin) (13-16). Synaptic and nonsynaptic transmission involving the release of neuropeptides and neurotransmitters, especially in hypothalamic areas controlling eating behavior and energy balance, are involved too (17)(18)(19).In excitable cells, the release of messenger molecules is a consequence of regulated membrane fusion and involves soluble N-ethylmaleimide-sensitive factor attachment proteins (SNAREs) (20, 21), including synaptosomal-associated protein of 25 kDa (SNAP-25). SNAP-25 is expressed as two developmentally regulated and alternatively spliced isoforms, SNAP-25a and SNAP-25b, which differ in only 9 of 206 amino acids (22, 23). In the mouse brain, SNAP-25a precedes SNAP-25b expression during development, but by the second postnatal week SNAP-25b becomes the major splice variant, concomitantly with a dr...

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The human L-type calcium channel Cav1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes

Cited by 79 publications

References 54 publications

Glucagon‑like peptide‑1 potentiates glucose‑stimulated insulin secretion via the transient receptor potential melastatin 2 channel

Glucagon‑like peptide‑1 potentiates glucose‑stimulated insulin secretion via the transient receptor potential melastatin 2 channel

Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

Replacing SNAP-25b with SNAP-25a expression results in metabolic disease

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