Alterations in Calcium Channel Currents Underlie Defective Insulin Secretion in a Transgenic Mouse

Jan, Chung-Ren; Ribar, Thomas J.; Means, Anthony R.; Augustine, George J

doi:10.1074/jbc.271.26.15478

Cited by 6 publications

(5 citation statements)

References 45 publications

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“…The Ca 2ϩ channels affected by the CaM-8 mutation are the L-type Ca 2ϩ channels because dihydropyridines blocked these currents (50). It is of interest that previous patch clamp studies using GH3 pituitary cells stably transfected with calbindin found that calbindin reduces Ca 2ϩ influx through voltage dependent L-type Ca 2ϩ channels (51).…”

Section: Discussionmentioning

confidence: 99%

“…Further studies were done on another mouse transgenic line, referred to as CaM-8. CaM-8 expresses in its ␤ cells a mutant form of calmodulin that is functionally similar to calbindin because it binds calcium with high affinity, and, unlike calmodulin but similar to calbindin, it does not activate effector proteins such as protein phosphatases and kinases (49,50). The CaM-8 transgenic mice also display defective insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

“…However the mechanism responsible for the underlying defect in insulin secretion is different than the mechanism reported for the CaM mice. The primary defect in the CaM-8 mice is not a defect in glucose utilization but rather a reduction in Ca 2ϩ current flowing through voltage-gated calcium channels resulting in a reduction in the rise in [Ca 2ϩ ] i (50). CaM-8 mice showed a marked attenuation in the elevation in [Ca 2ϩ ] i observed in response to depolarizing concentrations of KCl (50), similar to the attenuation observed in our studies in isolated islets and in ␤ cells overexpressing calbindin.…”

Section: Discussionmentioning

confidence: 99%

“…The primary defect in the CaM-8 mice is not a defect in glucose utilization but rather a reduction in Ca 2ϩ current flowing through voltage-gated calcium channels resulting in a reduction in the rise in [Ca 2ϩ ] i (50). CaM-8 mice showed a marked attenuation in the elevation in [Ca 2ϩ ] i observed in response to depolarizing concentrations of KCl (50), similar to the attenuation observed in our studies in isolated islets and in ␤ cells overexpressing calbindin. Further, patch clamp measurements using ␤ cells from CaM-8 mice revealed a significant decline in the peak amplitude of voltage-gated Ca 2ϩ channel currents.…”

Section: Discussionmentioning

confidence: 99%

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Calbindin-D28k Controls [Ca2+] and Insulin Release

Sooy¹,

Schermerhorn²,

Noda³

et al. 1999

Journal of Biological Chemistry

114

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Calbindin-D 28k is a 28,000 M r calcium-binding protein initially identified in avian intestine and was the first known target of vitamin D action (1). Calbindin has since been reported in many other tissues including kidney and bone and in tissues that are not primary regulators of serum calcium such as brain and pancreas (2-4). This calcium-binding protein has been conserved during evolution and is regulated by a number of different hormones and factors (3, 4). Calbindin-D 28k , a predominantly cytosolic protein, is a member of a family of high affinity calcium-binding proteins that includes calmodulin, S100 protein, and parvalbumin (5). It has been suggested that the role of calbindin in kidney and intestine is to facilitate transcellular calcium diffusion (6, 7). In brain, calbindin is not vitamin D-dependent and its proposed function is to buffer calcium, resulting in protection against calcium-mediated neurotoxicity (8, 9). In 1979 the discovery in the pancreas of a high affinity receptor for the hormonally active form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), was the first demonstration of a nonclassical target tissue to contain vitamin D receptors (10). Further autoradiographic and immunohistochemical analyses have shown that vitamin D receptors and calbindin-D 28k are both localized in the ␤ cell (11-13). Although these studies and others (14 -17) established a link between the pancreatic ␤ cell and the vitamin D endocrine system and although the importance of calcium in insulin secretion is well known, there is still little information available concerning the exact mechanism whereby vitamin D may affect ␤ cell function. It has been suggested that the role of vitamin D in calcium metabolism of the ␤ cell may involve a genomic effect of 1,25-(OH) 2 D 3 , including the production of calbindin.Although isolated islets and perfused pancreas from vitamin D-deficient animals have previously been used to study the effects of 1,25-(OH) 2 D 3 on ␤ cell function (14 -17), recently we reported that the ␤ cell line R1N1046-38 contains both calbindin and receptors for 1,25-(OH) 2 D 3 and suggested that ␤ cell lines may provide a useful in vitro system for studying the effects of the vitamin D endocrine system on ␤ cell function (18,19). Although interesting data have been generated in numerous studies using RIN cells, the RIN cell line may not be the best model because these cells have little or no response to glucose and the insulin content of these cells is only approximately 0.1% of the insulin content found in the normal ␤ cell.In this study, to understand the role of calbindin-D 28k in the pancreatic ␤ cells, calbindin was transfected and overexpressed in ␤HC and ␤TC cells, pancreatic ␤ cells that secrete insulin in a regulated manner and at levels more comparable with those of normal ␤ cells. Both cell lines are derived from transgenic mice that express the SV40 T-antigen in ␤ cells under the

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Calbindin-D28k Controls [Ca2+] and Insulin Release

Sooy¹,

Schermerhorn²,

Noda³

et al. 1999

Journal of Biological Chemistry

114

View full text Add to dashboard Cite

show abstract

“…Ankyrin G also associates with skeletal muscle postsynaptic membranes and sarcoplasmic reticulum (38), and CaMKII participates in regulating local [Ca 2ϩ ] gradients in subcellular zones involved in Ca 2ϩ signaling. CaMKII is an important Ca 2ϩ signaling effector and serves as a gauge that temporally integrates [Ca 2ϩ ] signal intensities (39), and calmodulin participates in several Ca 2ϩ -dependent processes in insulin secretion by ␤-cells (40,41). Calmodulin and iPLA 2 ␤ interact functionally (2,8,23,24,33), and the iPLA 2 ␤ domain from residues 650 -722 contains a calmodulin binding site (2).…”

mentioning

confidence: 99%

Group VIA Phospholipase A2 Forms a Signaling Complex with the Calcium/Calmodulin-dependent Protein Kinase IIβ Expressed in Pancreatic Islet β-Cells

Wang

Ramanadham

Alex

et al. 2005

Journal of Biological Chemistry

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Insulin-secreting pancreatic islet ␤-cells express a Group VIA Ca 2؉ -independent phospholipase A 2 (iPLA 2 ␤) that contains a calmodulin binding site and protein interaction domains. We identified Ca 2؉ /calmodulindependent protein kinase II␤ (CaMKII␤) as a potential iPLA 2 ␤-interacting protein by yeast two-hybrid screening of a cDNA library using iPLA 2 ␤ cDNA as bait. Cloning CaMKII␤ cDNA from a rat islet library revealed that one dominant CaMKII␤ isoform mRNA is expressed by adult islets and is not observed in brain or neonatal islets and that there is high conservation of the isoform expressed by rat and human ␤-cells. Binary two-hybrid assays using DNA encoding this isoform as bait and iPLA 2 ␤ DNA as prey confirmed interaction of the enzymes, as did assays with CaMKII␤ as prey and iPLA 2 ␤ bait. His-tagged CaMKII␤ immobilized on metal affinity matrices bound iPLA 2 ␤, and this did not require exogenous calmodulin and was not prevented by a calmodulin antagonist or the Ca 2؉ chelator EGTA. Activities of both enzymes increased upon their association, and iPLA 2 ␤ reaction products reduced CaMKII␤ activity. Both the iPLA 2 ␤ inhibitor bromoenol lactone and the CaMKII␤ inhibitor KN93 reduced arachidonate release from INS-1 insulinoma cells, and both inhibit insulin secretion. CaMKII␤ and iPLA 2 ␤ can be coimmunoprecipitated from INS-1 cells, and forskolin, which amplifies glucose-induced insulin secretion, increases the abundance of the immunoprecipitatable complex. These findings suggest that iPLA 2 ␤ and CaMKII␤ form a signaling complex in ␤-cells, consistent with reports that both enzymes participate in insulin secretion and that their expression is coinduced upon differentiation of pancreatic progenitor to endocrine progenitor cells.Phospholipases A 2 (PLA 2 ) 1 are a diverse group of enzymes that catalyze hydrolysis of sn-2 fatty acid substituents from glycerophospholipid substrates to yield a free fatty acid and a 2-lysophospholipid (1). The Group VIA PLA 2 designated iPLA 2 ␤ has a molecular mass of 84 -88 kDa and does not require Ca 2ϩ for catalysis (2). Various splice variants of iPLA 2 ␤ are expressed at high levels in testis (3), brain (4), and pancreatic islet ␤-cells (5), among other tissues.Certain nutrients, hormones, neurotransmitters, and pharmacologic agents stimulate insulin secretion from ␤-cells, and the dominant physiologic insulin secretagogue is D-glucose. A series of signals that result from glucose-induced ATP production and alterations of intracellular redox potentials trigger insulin secretion via a rise in cytosolic [Ca 2ϩ ], and Ca 2ϩ /calmodulin-dependent protein kinase II (CaMKII) is an important ␤-cell [Ca 2ϩ ] sensor and mediator of Ca 2ϩ -dependent events in insulin secretion (6 -11). Much evidence (12-22) suggests that iPLA 2 ␤ also participates in insulin secretion, including the facts that the mechanism-based bromoenol lactone (BEL) inhibitor of iPLA 2 ␤ suppresses glucose-induced hydrolysis of arachidonate from islet membrane phospholipids, the rise in ␤-cell cytosolic...

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Ions, genes and insulin release: from basic science to clinical disease Based on the 1998 R. D. Lawrence Lecture

Mj¹

2000

Diabetic Medicine

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In 1968, reports of the first microelectrode recordings of insulin-secreting cells were published. Thirty years later it is now established that electrical responses of beta-cells play a critical role in stimulus-secretion coupling. It is now also clear that defects in ion channel genes compromise the mechanisms which govern secretion and lead to the onset of disease. Here, the physiology of insulin release is reviewed in the context of ion channels, the ionic control of insulin release and the pathophysiology of hyperinsulinism of infancy.

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Alterations in Calcium Channel Currents Underlie Defective Insulin Secretion in a Transgenic Mouse

Abstract: A transgenic mouse overexpressing a mutant form of calmodulin (CaM-8) that is selectively targeted to pancreatic beta-cells has an impaired ability to secrete insulin in response to elevated blood glucose.

Cited by 6 publications

References 45 publications

Calbindin-D28k Controls [Ca2+] and Insulin Release

Calbindin-D28k Controls [Ca2+] and Insulin Release

Group VIA Phospholipase A2 Forms a Signaling Complex with the Calcium/Calmodulin-dependent Protein Kinase IIβ Expressed in Pancreatic Islet β-Cells

Ions, genes and insulin release: from basic science to clinical disease Based on the 1998 R. D. Lawrence Lecture

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