Intracellular Calcium Ion Response to Glucose in β-Cells of Calbindin-D&lt;sub&gt;28k&lt;/sub&gt; Nullmutant Mice and in βHC13 Cells Overexpressing Calbindin-D&lt;sub&gt;28k&lt;/sub&gt;

Parkash, Jyoti; Chaudhry, Muhammad Anwar; Amer, Ayman; Christakos, Sylvia; Rhoten, William B.

doi:10.1385/endo:18:3:221

Cited by 24 publications

(24 citation statements)

References 56 publications

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“…These results are in line with earlier reports on the reduction of insulin secretion from rat b-cells treated with inhibitors of TG2 transamidation activity (Bungay et al 1986, Driscoll et al 1997. However, the increase in Ca 2C level that leads to insulin secretion in b-cells in response to glucose is much lower (w150-250 nM) than the level of Ca 2C (w150-500 mM) required for TG2 transamidation activity (Lai et al 1997, Parkash et al 2002. In addition, intracellular levels of GTP, which is known to inhibit transamidation activity, are many fold higher (w100 mM) than Ca 2C levels (Siegel & Khosla 2007).…”

supporting

confidence: 92%

Functional characterization of naturally occurring transglutaminase 2 mutants implicated in early-onset type 2 diabetes

Salter¹,

Ande²,

Nguyen³

et al. 2012

Journal of Molecular Endocrinology

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Transglutaminase 2 (TG2) is an enzyme with diverse biological functions. TG2 catalyzes transamidation reactions, has intrinsic kinase activity, and acts as a G-protein in intracellular signaling. TG2 (Tgm2)-null mice are glucose intolerant and have impaired glucose-stimulated insulin secretion (GSIS). Furthermore, three naturally occurring missense mutations in the human TGM2 gene, corresponding to amino acid substitutions of Met330Arg, Ile331Asn, and Asn333Ser in the TG2 protein, have been reported and found to be associated with early-onset type 2 diabetes. However, their effect on TG2 function is not fully understood. To determine this, we have reproduced naturally occurring mutations in TG2 using site-directed mutagenesis. Overexpression of Myc-TG2 mutants in INS-1E cells resulted in a reduction of GSIS in comparison with cells overexpressing wild-type Myc-TG2 (WT-TG2). The maximum reduction was found in cells overexpressing Ile331Asn-TG2 (32%) followed by Met330Arg-TG2 (20%), and the least in Asn333Ser-TG2 (7%). Enzymatic analysis revealed that TG2 mutants have impaired transamidation and kinase activities in comparison with WT-TG2. GTP-binding assays showed that TG2 mutants also have altered GTP-binding ability, which is found to be modulated in response to glucose stimulation. Collectively, these data suggest that naturally occurring mutations in TG2 affect transamidation, kinase, and GTP-binding functions of TG2. While reduced insulin secretion, as a result of naturally occurring mutations in TG2, is due to the impairment of more than one biological function of TG2, it is the transamidation function that appears to be impaired during the first phase, whereas the GTP-binding function affects the second phase of insulin secretion.

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supporting

confidence: 92%

Functional characterization of naturally occurring transglutaminase 2 mutants implicated in early-onset type 2 diabetes

Salter¹,

Ande²,

Nguyen³

et al. 2012

Journal of Molecular Endocrinology

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“…In addition to a Ca 2+ -scavenging effect, accumulating evidence suggests that calbindin1 reduces Ca 2+ currents via an association with L-type VDDCs [29]. Glucose-and Ca 2+ -dependent translocation of calbindin1 to the plasma membrane has previously been suggested to facilitate the interaction with L-type Ca 2+ channels [28,29]. This could explain the lack of effect on the capacitance increase evoked by the first depolarisation (Figs 2c and 4e), because the first influx of Ca 2+ would induce translocation of calbindin1 to the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

“…We observed no regulation of BMP receptors or L-type Ca 2+ channel subunits. One of the most strongly regulated genes was Calb1, which encodes an EF-hand Ca 2+ -binding protein previously shown to regulate Ca 2+ currents through VDCC and inhibit GSIS in beta cells [27][28][29]. BMP4 increased the expression of Calb1 mRNA by sixfold in neonatal rat islets, resulting in a 2.5-fold increase in calbindin1 protein after 96 h (Fig.…”

Section: Bmp4 Mediates Upregulation Of Calbindin1mentioning

confidence: 99%

Bone morphogenetic protein 4 inhibits insulin secretion from rodent beta cells through regulation of calbindin1 expression and reduced voltage-dependent calcium currents

et al. 2015

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Aims/hypothesis Type 2 diabetes is characterised by progressive loss of pancreatic beta cell mass and function. Therefore, it is of therapeutic interest to identify factors with the potential to improve beta cell proliferation and insulin secretion. Bone morphogenetic protein 4 (BMP4) expression is increased in diabetic animals and BMP4 reduces glucose-stimulated insulin secretion (GSIS). Here, we investigate the molecular mechanism behind this inhibition. Methods BMP4-mediated inhibition of GSIS was investigated in detail using single cell electrophysiological measurements and live cell Ca 2+ imaging. BMP4-mediated gene expression changes were investigated by microarray profiling, quantitative PCR and western blotting.Results Prolonged exposure to BMP4 reduced GSIS from rodent pancreatic islets. This inhibition was associated with decreased exocytosis due to a reduced Ca 2+ current through voltage-dependent Ca 2+ channels. To identify proteins involved in the inhibition of GSIS, we investigated global gene expression changes induced by BMP4 in neonatal rat pancreatic islets. Expression of the Ca 2+ -binding protein calbindin1 was significantly induced by BMP4. Overexpression of calbindin1 in primary islet cells reduced GSIS, and the effect of BMP4 on GSIS was lost in islets from calbindin1 (Calb1) knockout mice. Conclusions/interpretation We found BMP4 treatment to markedly inhibit GSIS from rodent pancreatic islets in a calbindin1-dependent manner. Calbindin1 is suggested to mediate the effect of BMP4 by buffering Ca 2+ and decreasing Ca 2+ channel activity, resulting in diminished insulin exocytosis. Both BMP4 and calbindin1 are potential pharmacological targets for the treatment of beta cell dysfunction.

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“…In brain and pancreas, calbindin-D 28k is colocalized with L-type calcium channels [21,22]. In duodenum and jejunum calbindin-D 9k is colocalized with the epithelial calcium channel TRPV6 and in the kidney calbindin-D 28k is colocalized with the epithelial calcium channel TRPV5 [23].…”

Section: Calbindinmentioning

confidence: 99%

New insights into the function and regulation of vitamin D target proteins

Christakos

Dhawan

Peng

et al. 2007

The Journal of Steroid Biochemistry and Molecular Biology

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Calbindin-D 28k has been reported to be a facilitator of calcium diffusion and to protect against apoptotic cell death. Most recently we found that the presence of calbindin-D 28k results in reduced calcium influx through voltage-dependent L-type Ca 2+ channels and enhanced sensitivity of the channels to calcium dependent inactivation. Co-immunoprecipitation and GST pull down assays indicate that calbindin-D 28k interacts with the C-terminus of the L-type calcium channel alpha 1c subunit (Ca v 1.2). This is the first report of the binding of calbindin to a calcium channel and provides new insight concerning mechanisms by which calbindin acts to modulate intracellular calcium. Besides calbindin, another major target of 1,25(OH) 2 D 3 is 24(OH)ase, which is involved in the catabolism of 1,25(OH) 2 D 3 . We reported that C/EBPβ is a major transcriptional activator of 24(OH)ase that cooperates with CBP/p300 in regulating VDR mediated 24(OH)ase transcription. Recently we found, in addition to p160 coactivators, that SWI/SNF complexes (that facilitate transcription by remodeling chromatin using the energy of ATP hydrolysis) are also involved in VDR mediated 24(OH)ase transcription and functionally cooperate with C/EBPβ in regulating 24(OH)ase. These findings define novel mechanisms that may be of fundamental importance in understanding how 1,25(OH) 2 D 3 mediates its multiple biological effects. Keywordscalbindin-D 28k ; L type calcium channels; 25-hydroxyvitamin D3 24-hydroxylase; CCAAT enhancer binding protein; SWI/SNF chromatin remodeling complex

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Intracellular Calcium Ion Response to Glucose in β-Cells of Calbindin-D<sub>28k</sub> Nullmutant Mice and in βHC13 Cells Overexpressing Calbindin-D<sub>28k</sub>

Cited by 24 publications

References 56 publications

Functional characterization of naturally occurring transglutaminase 2 mutants implicated in early-onset type 2 diabetes

Functional characterization of naturally occurring transglutaminase 2 mutants implicated in early-onset type 2 diabetes

Bone morphogenetic protein 4 inhibits insulin secretion from rodent beta cells through regulation of calbindin1 expression and reduced voltage-dependent calcium currents

New insights into the function and regulation of vitamin D target proteins

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