Opposite Effects of Glucose on Plasma Membrane Ca2+-ATPase and Na/Ca Exchanger Transcription, Expression, and Activity in Rat Pancreatic β-Cells

Ximenes, Helena Maria; Kamagaté, Adama; Eylen, Françoise Van; Carpinelli, Ângelo Rafael; Herchuelz, A.

doi:10.1074/jbc.m212339200

Cited by 19 publications

(22 citation statements)

References 37 publications

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“…6B), which may perturb glucose-stimulated insulin secretion (Roe et al 1994; Marie et al 2001). In addition, we report for the first time a 30% increase in NCX activity in db/db beta-cells, which is consistent with the enhancement of NCX transcription observed in islets cultured in high glucose (Ximenes et al 2003). Thus our data generally agree with previous studies conducted in this field.…”

Section: Discussionsupporting

confidence: 91%

“…SERCA pump defects combined with an up-regulation of NCX function often result in reduced uptake of Ca 2+ to ER calcium stores (Ximenes et al 2003), and alterations in ER permeability during diabetes have been suggested (Islam 2002). To quantitatively evaluate the Ca 2+ content in the ER and its permeability, we modified a protocol from a previous study conducted in sympathetic neurons (Albrecht et al 2002).…”

Section: Resultsmentioning

confidence: 99%

“…However, SERCA3-specific knockout (KO) mice are normoglycemic and have normal insulinemia (Arredouani et al 2002). PMCA activity is down-regulated in certain types of diabetic islets (Roe et al 1994; Hoenig et al 1990; Levy et al 1998), in contrast to beta-cells cultured under high glucose conditions, which exhibited enhanced NCX transcription (Ximenes et al 2003). These controversies can only be resolved if the functions of different Ca 2+ signaling proteins in normal and diabetic beta-cells are systematically compared under identical experimental conditions.…”

Section: Introductionmentioning

confidence: 99%

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Alterations of the Ca2+ signaling pathway in pancreatic beta-cells isolated from db/db mice

et al. 2014

Protein Cell

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Upon glucose elevation, pancreatic beta-cells secrete insulin in a Ca2+-dependent manner. In diabetic animal models, different aspects of the calcium signaling pathway in beta-cells are altered, but there is no consensus regarding their relative contributions to the development of beta-cell dysfunction. In this study, we compared the increase in cytosolic Ca2+ ([Ca2+]i) via Ca2+ influx, Ca2+ mobilization from endoplasmic reticulum (ER) calcium stores, and the removal of Ca2+ via multiple mechanisms in beta-cells from both diabetic db/db mice and non-diabetic C57BL/6J mice. We refined our previous quantitative model to describe the slow [Ca2+]i recovery after depolarization in beta-cells from db/db mice. According to the model, the activity levels of the two subtypes of the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) pump, SERCA2 and SERCA3, were severely down-regulated in diabetic cells to 65% and 0% of the levels in normal cells. This down-regulation may lead to a reduction in the Ca2+ concentration in the ER, a compensatory up-regulation of the plasma membrane Na+/Ca2+ exchanger (NCX) and a reduction in depolarization-evoked Ca2+ influx. As a result, the patterns of glucose-stimulated calcium oscillations were significantly different in db/db diabetic beta-cells compared with normal cells. Overall, quantifying the changes in the calcium signaling pathway in db/db diabetic beta-cells will aid in the development of a disease model that could provide insight into the adaptive transformations of beta-cell function during diabetes development.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-014-0075-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Alterations of the Ca2+ signaling pathway in pancreatic beta-cells isolated from db/db mice

et al. 2014

Protein Cell

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“…Glucose metabolism could increase the activity of L-type Ca 2+ channels [8, 9], influence Ca 2+ handling by intracellular Ca 2+ stores [10] and modulate the rate of Ca 2+ extrusion through the plasma membrane [11]. As yet undetected [Ca 2+ ] changes confined to subplasma membrane domains where Ca 2+ -dependent exocytosis takes place [12–17] might therefore account for the apparent amplification phenomenon.…”

Section: Introductionmentioning

confidence: 99%

Subplasmalemmal Ca2+ measurements in mouse pancreatic beta cells support the existence of an amplifying effect of glucose on insulin secretion

Ravier¹,

Cheng-Xue²,

Palmer

et al. 2010

Diabetologia

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Aims/hypothesis Glucose-induced insulin secretion is attributed to a rise of beta cell cytosolic free [Ca2+] ([Ca2+]c) (triggering pathway) and amplification of the action of Ca2+. This concept of amplification rests on observations that glucose can increase Ca2+-induced insulin secretion without further elevating an imposed already high [Ca2+]c. However, it remains possible that this amplification results from an increase in [Ca2+] just under the plasma membrane ([Ca2+]SM), which escaped detection by previous measurements of global [Ca2+]c. This was the hypothesis that we tested here by measuring [Ca2+]SM. Methods The genetically encoded Ca2+ indicators D3-cpv (untargeted) and LynD3-cpv (targeted to plasma membrane) were expressed in clusters of mouse beta cells. LynD3-cpv was also expressed in beta cells within intact islets. [Ca2+]SM changes were monitored using total internal reflection fluorescence microscopy. Insulin secretion was measured in parallel. Results Beta cells expressing D3cpv or LynD3cpv displayed normal [Ca2+] changes and insulin secretion in response to glucose. Distinct [Ca2+]SM fluctuations were detected during repetitive variations of KCl between 30 and 32–35 mmol/l, attesting to the adequate sensitivity of our system. When the amplifying pathway was evaluated (high KCl+diazoxide), increasing glucose from 3 to 15 mmol/l consistently lowered [Ca2+]SM while stimulating insulin secretion approximately two fold. Blocking Ca2+ uptake by the endoplasmic reticulum largely attenuated the [Ca2+]SM decrease produced by high glucose but did not unmask localised [Ca2+]SM increases. Conclusions/interpretation Glucose can increase Ca2+-induced insulin secretion without causing further elevation of beta cell [Ca2+]SM. The phenomenon is therefore a true amplification of the triggering action of Ca2+.

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“…It has been found that c-myc was able to repress PMCA4 expression during activation of B lymphocytes, which additionally resulted in decreased Ca 2+ clearance, and interestingly, in an augmented NFAT level [65]. A similar research has been conducted in pancreatic β cells showing that c-myc expression has led to downregulation of PMCA1 and PMCA2 [66], [67]. Important data, showing that PMCA4 expression could be induced by NFAT1c in osteoclasts during the growth of bone mass, have been provided recently [43].…”

Section: Discussionmentioning

confidence: 85%

NFAT1 and NFAT3 Cooperate with HDAC4 during Regulation of Alternative Splicing of PMCA Isoforms in PC12 Cells

Kosiorek

Podszywałow-Bartnicka

Żylińska

et al. 2014

PLoS ONE

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BackgroundThe bulk of human genes undergo alternative splicing (AS) upon response to physiological stimuli. AS is a great source of protein diversity and biological processes and is associated with the development of many diseases. Pheochromocytoma is a neuroendocrine tumor, characterized by an excessive Ca2+-dependent secretion of catecholamines. This underlines the importance of balanced control of calcium transport via regulation of gene expression pattern, including different calcium transport systems, such as plasma membrane Ca2+-ATPases (PMCAs), abundantly expressed in pheochromocytoma chromaffin cells (PC12 cells). PMCAs are encoded by four genes (Atp2b1, Atp2b2, Atp2b3, Atp2b4), whose transcript products undergo alternative splicing giving almost 30 variants.ResultsIn this scientific report, we propose a novel mechanism of regulation of PMCA alternative splicing in PC12 cells through cooperation of the nuclear factor of activated T-cells (NFAT) and histone deacetylases (HDACs). Luciferase assays showed increased activity of NFAT in PC12 cells, which was associated with altered expression of PMCA. RT-PCR experiments suggested that inhibition of the transcriptional activity of NFAT might result in the rearrangement of PMCA splicing variants in PC12 cells. NFAT inhibition led to dominant expression of 2x/c, 3x/a and 4x/a PMCA variants, while in untreated cells the 2w,z/b, 3z,x/b,c,e,f, and 4x/b variants were found as well. Furthermore, chromatin immunoprecipitation experiments showed that NFAT1-HDAC4 or NFAT3-HDAC4 complexes might be involved in regulation of PMCA2x splicing variant generation.ConclusionsWe suggest that the influence of NFAT/HDAC on PMCA isoform composition might be important for altered dopamine secretion by PC12 cells.

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Opposite Effects of Glucose on Plasma Membrane Ca2+-ATPase and Na/Ca Exchanger Transcription, Expression, and Activity in Rat Pancreatic β-Cells

Cited by 19 publications

References 37 publications

Alterations of the Ca2+ signaling pathway in pancreatic beta-cells isolated from db/db mice

Alterations of the Ca2+ signaling pathway in pancreatic beta-cells isolated from db/db mice

Subplasmalemmal Ca2+ measurements in mouse pancreatic beta cells support the existence of an amplifying effect of glucose on insulin secretion

NFAT1 and NFAT3 Cooperate with HDAC4 during Regulation of Alternative Splicing of PMCA Isoforms in PC12 Cells

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