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• W2002602258 abstract "The role of the calcium-binding protein, calbindin-D28k in potassium/depolarization-stimulated increases in the cytosolic free Ca2+ concentration ([Ca2+]i) and insulin release was investigated in pancreatic islets from calbindin-D28k nullmutant mice (knockouts; KO) or wild type mice and β cell lines stably transfected and overexpressing calbindin. Using single islets from KO mice and stimulation with 45 mm KCl, the peak of [Ca2+]i was 3.5-fold greater in islets from KO mice compared with wild type islets (p < 0.01) and [Ca2+]i remained higher during the plateau phase. In addition to the increase in [Ca2+]i in response to KCl there was also a significant increase in insulin release in islets isolated from KO mice. Evidence for modulation by calbindin of [Ca2+]i and insulin release was also noted using β cell lines. Rat calbindin was stably expressed in βTC-3 and βHC-13 cells. In response to depolarizing concentrations of K+, insulin release was decreased by 45–47% in calbindin expressing βTC cells and was decreased by 70–80% in calbindin expressing βHC cells compared with insulin release from vector transfected βTC or βHC cells (p < 0.01). In addition, the K+-stimulated intracellular calcium peak was markedly inhibited in calbindin expressing βHC cells compared with vector transfected cells (225 nm versus1,100 nm, respectively). Buffering of the depolarization-induced rise in [Ca2+]i was also observed in calbindin expressing βTC cells. In summary, our findings, using both isolated islets from calbindin-D28k KO mice and β cell lines, establish a role for calbindin in the modulation of depolarization-stimulated insulin release and suggest that calbindin can control the rate of insulin release via regulation of [Ca2+]i. The role of the calcium-binding protein, calbindin-D28k in potassium/depolarization-stimulated increases in the cytosolic free Ca2+ concentration ([Ca2+]i) and insulin release was investigated in pancreatic islets from calbindin-D28k nullmutant mice (knockouts; KO) or wild type mice and β cell lines stably transfected and overexpressing calbindin. Using single islets from KO mice and stimulation with 45 mm KCl, the peak of [Ca2+]i was 3.5-fold greater in islets from KO mice compared with wild type islets (p < 0.01) and [Ca2+]i remained higher during the plateau phase. In addition to the increase in [Ca2+]i in response to KCl there was also a significant increase in insulin release in islets isolated from KO mice. Evidence for modulation by calbindin of [Ca2+]i and insulin release was also noted using β cell lines. Rat calbindin was stably expressed in βTC-3 and βHC-13 cells. In response to depolarizing concentrations of K+, insulin release was decreased by 45–47% in calbindin expressing βTC cells and was decreased by 70–80% in calbindin expressing βHC cells compared with insulin release from vector transfected βTC or βHC cells (p < 0.01). In addition, the K+-stimulated intracellular calcium peak was markedly inhibited in calbindin expressing βHC cells compared with vector transfected cells (225 nm versus1,100 nm, respectively). Buffering of the depolarization-induced rise in [Ca2+]i was also observed in calbindin expressing βTC cells. In summary, our findings, using both isolated islets from calbindin-D28k KO mice and β cell lines, establish a role for calbindin in the modulation of depolarization-stimulated insulin release and suggest that calbindin can control the rate of insulin release via regulation of [Ca2+]i. 1-isobutyl-3-methylxanthine 12-O-tetra-decanoylphorbol-13-acetate polymerase chain reaction knockout wild type 25-(OH)2D3, 1,25-dihydroxyvitamin D3 Calbindin-D28k is a 28,000 M rcalcium-binding protein initially identified in avian intestine and was the first known target of vitamin D action (1Wasserman R.H. Taylor A.N. Science. 1966; 152: 791-793Crossref PubMed Scopus (405) Google Scholar). 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 (2Christakos S. Gabrielides C. Rhoten W.B. Endocr. Rev. 1989; 10: 3-26Crossref PubMed Scopus (398) Google Scholar, 3Christakos S. Endocr. Rev. Monograph. 1995; 4: 108-110Google Scholar, 4Christakos S. Beck J.D. Hyllner S.J. Feldman D. Glorieux F. Pike J.W. Vitamin D. Academic Press, San Francisco, CA1997: 209-221Google Scholar). This calcium-binding protein has been conserved during evolution and is regulated by a number of different hormones and factors (3Christakos S. Endocr. Rev. Monograph. 1995; 4: 108-110Google Scholar, 4Christakos S. Beck J.D. Hyllner S.J. Feldman D. Glorieux F. Pike J.W. Vitamin D. Academic Press, San Francisco, CA1997: 209-221Google Scholar). Calbindin-D28k, a predominantly cytosolic protein, is a member of a family of high affinity calcium-binding proteins that includes calmodulin, S100 protein, and parvalbumin (5Heizmann C.W. Hunziker W. Trends Biochem. Sci. 1991; 16: 98-103Abstract Full Text PDF PubMed Scopus (403) Google Scholar). It has been suggested that the role of calbindin in kidney and intestine is to facilitate transcellular calcium diffusion (6Feher J.J. Am. J. Physiol. 1983; 244: C303-C307Crossref PubMed Google Scholar, 7Bronner F. Am. J. Physiol. 1989; 257: F707-F711PubMed Google Scholar). In brain, calbindin is not vitamin D-dependent and its proposed function is to buffer calcium, resulting in protection against calcium-mediated neurotoxicity (8Mattson M.P. Rychlik B. Chu C. Christakos S. Neuron. 1991; 6: 41-51Abstract Full Text PDF PubMed Scopus (485) Google Scholar, 9Guo Q. Christakos S. Robinson N. Mattson M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3227-3232Crossref PubMed Scopus (204) Google Scholar).In 1979 the discovery in the pancreas of a high affinity receptor for the hormonally active form of vitamin D, 1,25- dihydroxyvitamin D3 (1,25(OH)2D3), was the first demonstration of a nonclassical target tissue to contain vitamin D receptors (10Christakos S. Norman A.W. Biochem. Biophys. Res. Commun. 1979; 89: 56-63Crossref PubMed Scopus (105) Google Scholar). Further autoradiographic and immunohistochemical analyses have shown that vitamin D receptors and calbindin-D28k are both localized in the β cell (11Clark S.A. Stumpf W.E. Sar M. DeLuca H.F. Tanaka Y. Cell Tissue Res. 1980; 209: 515-520Crossref PubMed Scopus (119) Google Scholar, 12Roth J. Bonner-Weir S. Norman A.W. Orci L. Endocrinology. 1982; 110: 2216-2218Crossref PubMed Scopus (99) Google Scholar, 13Johnson J.A. Grande J.P. Roche P. Kumar R. Am. J. Physiol. 1994; 267: E356-E360PubMed Google Scholar). Although these studies and others (14Norman A.W. Frankel B.J. Heldt A.M. Grodsky G.M. Science. 1980; 209: 823-825Crossref PubMed Scopus (585) Google Scholar, 15Clark S.A. Stumpf W.E. Sar M. Diabetes. 1981; 30: 382-386Crossref PubMed Scopus (0) Google Scholar, 16Chertow B.S. Sivitz W.I. Baranetsky N.G. Clark S.A. Waite A. DeLuca H.F. Endocrinology. 1983; 113: 1511-1518Crossref PubMed Scopus (163) Google Scholar, 17Kadowaki S. Norman A.W. J. Clin. Invest. 1984; 73: 759-766Crossref PubMed Scopus (183) Google Scholar) established a link between the pancreatic β 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 β cell function. It has been suggested that the role of vitamin D in calcium metabolism of the β cell may involve a genomic effect of 1,25-(OH)2D3, 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)2D3 on β cell function (14Norman A.W. Frankel B.J. Heldt A.M. Grodsky G.M. Science. 1980; 209: 823-825Crossref PubMed Scopus (585) Google Scholar, 15Clark S.A. Stumpf W.E. Sar M. Diabetes. 1981; 30: 382-386Crossref PubMed Scopus (0) Google Scholar, 16Chertow B.S. Sivitz W.I. Baranetsky N.G. Clark S.A. Waite A. DeLuca H.F. Endocrinology. 1983; 113: 1511-1518Crossref PubMed Scopus (163) Google Scholar, 17Kadowaki S. Norman A.W. J. Clin. Invest. 1984; 73: 759-766Crossref PubMed Scopus (183) Google Scholar), recently we reported that the β cell line R1N1046-38 contains both calbindin and receptors for 1,25-(OH)2D3and suggested that β cell lines may provide a useful in vitro system for studying the effects of the vitamin D endocrine system on β cell function (18Lee S. Clark S.A. Gill R.K. Christakos S. Endocrinology. 1994; 134: 1602-1610Crossref PubMed Scopus (145) Google Scholar, 19Reddy D. Pollock A.S. Clark S.A. Sooy K. Vasavada R.C. Stewart A.F. Honeyman T. Christakos S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1961-1966Crossref PubMed Scopus (30) Google Scholar). 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 β cell.In this study, to understand the role of calbindin-D28k in the pancreatic β cells, calbindin was transfected and overexpressed in βHC and βTC cells, pancreatic β cells that secrete insulin in a regulated manner and at levels more comparable with those of normal β cells. Both cell lines are derived from transgenic mice that express the SV40 T-antigen in β cells under the control of the insulin gene regulatory region (20D'Ambra R. Surana M. Efrat S. Starr R.G. Fleischer N. Endocrinology. 1990; 126: 2815-2822Crossref PubMed Scopus (96) Google Scholar, 21Efrat S. Leiser M. Surana M. Tal M. Fusco-Demane D. Fleischer N. Diabetes. 1993; 42: 901-907Crossref PubMed Scopus (90) Google Scholar, 22Radvanyi F. Christgau S. Baekkeskov S. Jolicoeur C. Hanahan D. Mol. Cell. Biol. 1993; 13: 4223-4232Crossref PubMed Google Scholar). In addition, calbindin-D28k nullmutant (or knockout) mice were also used because they provide a good model in which to examine the effect of complete ablation of calbindin in the pancreatic islet on insulin release. This study, which is the first to address the role of calbindin in the β cell using both islets and β cell lines, suggests that calbindin has an important role in controlling depolarization-induced increases in intracellular calcium and therefore insulin release from the pancretic β cell.DISCUSSIONIn this study we found that calbindin acts as a modulator of depolarization-induced calcium transients in the pancreatic β cell and that calbindin has a role in controlling depolarization-induced insulin release via regulation of [Ca2+]i. The data show that in islets isolated from calbindin-D28k KO mice, in addition to an increase in [Ca2+]i in response to KCl, there is also an increase in sustained insulin release when compared with WT islets. Although both the peak and plateau [Ca2+]i in response to KCl are significantly greater in the islets from KO mice, only the sustained phase of KCl-induced insulin release (and not peak insulin release) is significantly greater in islets from KO mice when compared with WT islets (Figs. 2 and 3). The most likely explanation of this finding is that 45 mm KCl increases [Ca2+]i in WT islets to a level that is sufficient to maximally induce first phase insulin release. The greater rise in peak [Ca2+]iobserved in the islets from the KO mice cannot result in a further increase in the first phase insulin release rate, although the sustained phase of insulin release (which may not be maximally induced in the WT islets) is significantly increased. Thus the role of calbindin may be as a modulator of the sustained phase of insulin release via regulation of [Ca2+]i. A role for calbindin in modulation of insulin release via regulation of [Ca2+]i was also noted in the studies using calbindin overexpressing β cells. In response to K+stimulation both the [Ca2+]i peak as well as insulin release are decreased or inhibited compared with β cells not expressing calbindin (Figs. 5, 6, 8, and 9). Thus the changes noted in insulin release from cells overexpressing calbindin and islets from KO mice as well as the presence of calbindin in the normal β cell strongly suggest that calbindin plays a role in normal insulin secretory physiology. Reduction of [Ca2+]itransients evoked by voltage depolarization has previously been observed to be a function of calbindin in neurons (24Airaksinen M.S. Eilers J. Garaschuk O. Thoenen H. Konnerth A. Meyer M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1488-1493Crossref PubMed Scopus (349) Google Scholar, 36Chard P.S. Bleakman D. Christakos S. Fullmer C.S. Miller R.J. J. Physiol. 1993; 472: 341-357Crossref PubMed Scopus (308) Google Scholar, 37Chard P.S. Jordan J. Marcuccilli C.J. Miller R.J. Leiden J.M. Roos R.P. Ghadge G.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5144-5148Crossref PubMed Scopus (107) Google Scholar). It was suggested that impaired motor coordination, which is the phenotype of the calbindin KO mice, may be the result of abnormal cerebellar activity because of altered depolarization-induced calcium transients in the Purkinje cells (24Airaksinen M.S. Eilers J. Garaschuk O. Thoenen H. Konnerth A. Meyer M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1488-1493Crossref PubMed Scopus (349) Google Scholar). Calbindin was also reported to play a role in the control of hypothalamic neuroendocrine neuronal firing patterns. Calbindin was introduced into rat supraoptic neurons using the whole cell patch clamp method. Calbindin suppressed Ca2+-dependent depolarization after-potentials, and it was suggested that calbindin, by regulating depolarization-induced potentials, may be involved in the control of hormone secretion from hypothalamic neuroendocrine neurons (38Li Z. Decavel C. Hatton G.I. J. Physiol. 1995; 488: 601-608Crossref PubMed Scopus (98) Google Scholar). Thus calbindin appears to act similarly in β cells and neurons. Functional and phenotypic similarities have previously been reported between neurons and pancreatic β cells. For example β cells, similar to neurons, express proteins and amino acids specialized for neurotransmission such as glutamate receptors, γ-aminobutyric acid and synapsin I (39Weaver C.D. Yao T.L. Powers A.C. Verdoorn T.A. J. Biol. Chem. 1996; 271: 12977-12984Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 40Rorsman P. Berggren P.O. Bokvist K. Ericson H. Mohler H. Ostenson C.G. Smith P.A. Nature. 1989; 341: 233-236Crossref PubMed Scopus (367) Google Scholar, 41Krueger K.A. Ings E.I. Brun A.-M. Landt M. Easom R.A. Diabetes. 1999; 48: 499-506Crossref PubMed Scopus (29) Google Scholar, 42Sorenson R.L. Garry D.G. Brelje T.C. Diabetes. 1991; 40: 1365-1374Crossref PubMed Scopus (137) Google Scholar, 43Santos R.M. Rosario L.M. Nadal A. Garcia-Sancho J. Soria B. Valdeolmillos M. Pfluegers Arch. Eur. J. Physiol. 1991; 418: 417-422Crossref PubMed Scopus (314) Google Scholar). Glutamate has been shown to induce depolarization in islets and currents evoked by glutamate in islets show properties very similar to currents induced in neurons (39Weaver C.D. Yao T.L. Powers A.C. Verdoorn T.A. J. Biol. Chem. 1996; 271: 12977-12984Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). It is of interest that in previous studies in neurons, calbindin has been reported to reduce [Ca2+]i in response to glutamate (8Mattson M.P. Rychlik B. Chu C. Christakos S. Neuron. 1991; 6: 41-51Abstract Full Text PDF PubMed Scopus (485) Google Scholar). Thus it is possible that calbindin may similarly modulate the rise [Ca2+]i in response not only to K+ but also to glutamate in the β cell. In our study we focused on the effect of calbindin on modulation of calcium transients in islets and β cell lines induced by depolarizing concentrations of KCl. Not much is known, however, about the ability of calbindin to modulate calcium influx in the β cell in response to other secretagogues. In one study using RIN1046-38 cells, induction of calbindin was shown to attenuate the [Ca2+]iresponse to the secretagogues glucose and KCl as well as to the calcium ionophore ionomycin and to thapsigargin (which releases Ca2+ from intracellular calcium stores) (44Rhoten W.B. Sergeev I.N. Endocrine. 1994; 2: 989-995Google Scholar). These studies, combined with our findings, suggest a basic role for calbindin in controlling various calcium fluxes in the β cell.In addition to calbindin, calmodulin (45Watkins D.T. Diabetes. 1991; 40: 1063-1068Crossref PubMed Google Scholar) and calcyclin (46Okazaki K. Niki I. Iino S. Kobayashi S. Hidaka H. J. Biol. Chem. 1994; 269: 6149-6152Abstract Full Text PDF PubMed Google Scholar) are two other calcium-binding proteins present in the β cell that have been reported to play a role, through their interaction with Ca2+, in modulating the insulin secretory response. Calcyclin, unlike calbindin, which acts as a Ca2+ buffer, was reported to enhance insulin release by a mechanism involving Ca2+-induced exocytosis (46Okazaki K. Niki I. Iino S. Kobayashi S. Hidaka H. J. Biol. Chem. 1994; 269: 6149-6152Abstract Full Text PDF PubMed Google Scholar). Studies using transgenic mice with the calcium-binding protein calmodulin overexpressed in the pancreatic β cells show that these mice (referred to as CaM mice) have decreased plasma insulin levels, leading to increased serum glucose levels and early onset of diabetes (47Epstein P.N. Overbeek P.A. Means A.R. Cell. 1989; 58: 1067-1073Abstract Full Text PDF PubMed Scopus (176) Google Scholar). Impairment in the metabolism of glucose and the subsequent generation of ATP was reported to be the underlying mechanism involved in the defective insulin secretion in the calmodulin transgenic mouse (48Ribar T.J. Jan C.-R. Augustine G.J. Means A.R. J. Biol. Chem. 1995; 270: 28688-28695Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). Further studies were done on another mouse transgenic line, referred to as CaM-8. CaM-8 expresses in its β 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 (49Ribar T.J. Epstein P.N. Overbeek P.A. Means A.R. Endocrinology. 1995; 136: 106-115Crossref PubMed Google Scholar, 50Jan C.-R. Ribar T.J. Means A.R. Augustine G.J. J. Biol. Chem. 1996; 271: 15478-15485Crossref PubMed Scopus (6) Google Scholar). The CaM-8 transgenic mice also display defective insulin secretion. 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 Ca2+ current flowing through voltage-gated calcium channels resulting in a reduction in the rise in [Ca2+]i (50Jan C.-R. Ribar T.J. Means A.R. Augustine G.J. J. Biol. Chem. 1996; 271: 15478-15485Crossref PubMed Scopus (6) Google Scholar). CaM-8 mice showed a marked attenuation in the elevation in [Ca2+]iobserved in response to depolarizing concentrations of KCl (50Jan C.-R. Ribar T.J. Means A.R. Augustine G.J. J. Biol. Chem. 1996; 271: 15478-15485Crossref PubMed Scopus (6) Google Scholar), similar to the attenuation observed in our studies in isolated islets and in β cells overexpressing calbindin. Further, patch clamp measurements using β cells from CaM-8 mice revealed a significant decline in the peak amplitude of voltage-gated Ca2+ channel currents. The Ca2+ channels affected by the CaM-8 mutation are the l-type Ca2+ channels because dihydropyridines blocked these currents (50Jan C.-R. Ribar T.J. Means A.R. Augustine G.J. J. Biol. Chem. 1996; 271: 15478-15485Crossref PubMed Scopus (6) Google Scholar). It is of interest that previous patch clamp studies using GH3 pituitary cells stably transfected with calbindin found that calbindin reduces Ca2+ influx through voltage dependent l-type Ca2+ channels (51Lledo P.M. Somasundaram B. Morton A.J. Emson P.C. Mason W.T. Neuron. 1992; 9: 943-954Abstract Full Text PDF PubMed Scopus (166) Google Scholar). In addition, immunohistochemical studies mapping calbindin in brain noted the similarity between the distribution of calbindin immunoreactivity and the distribution ofl-type calcium channels mapped using autoradiography (52Celio M.R. Neuroscience. 1990; 35: 375-475Crossref PubMed Scopus (1913) Google Scholar). Further studies are needed to determine (as suggested by our studies with KCl and the similarities observed between calbindin and CaM-8) whether calbindin can act not only as a buffer protein but also as a protein that can affect other Ca2+-regulating proteins such as Ca2+ channels not only in GH3 cells but also in β cells. In the future, it will be of interest to examine whether calbindin can modulate Ca2+ channel activity by a direct binding mechanism or whether calbindin can affect other proteins involved in regulating calcium channels.In addition to depolarizing concentrations of potassium, calbindin overexpression was also found to suppress insulin secretion in response to the phorbol ester TPA, which is known to activate certain forms of protein kinase C. TPA can stimulate insulin secretion in the presence or absence of basal glucose (35Yada T. Russo L.L. Sharp G.W.G. J. Biol. Chem. 1989; 264: 2455-2462Abstract Full Text PDF PubMed Google Scholar, 53Regazzi R. Li G. Deshusses J. Wollheim C.B. J. Biol. Chem. 1990; 265: 15003-15009Abstract Full Text PDF PubMed Google Scholar, 54Malaisse W.J. Sener A. Herchuelz A. Carpinelli A.R. Poloczek P. Winand J. Castagna M. Cancer Res. 1980; 40: 3827-3831PubMed Google Scholar). It has been suggested that phorbol ester-stimulated insulin secretion is linked with membrane depolarization and an increase in [Ca2+]i (35Yada T. Russo L.L. Sharp G.W.G. J. Biol. Chem. 1989; 264: 2455-2462Abstract Full Text PDF PubMed Google Scholar,55Arkhammar P. Juntti-Berggren L. Larsson O. Welsh M. Nanberg E. Sjöholm A. Kohler M. Berggren P.O. J. Biol. Chem. 1994; 269: 2743-2749Abstract Full Text PDF PubMed Google Scholar), similar to the effect of KCl. The Ca2+ channels responsible for the increased [Ca2+]i signal in response to TPA have been reported to be the l-type Ca2+ channels (35Yada T. Russo L.L. Sharp G.W.G. J. Biol. Chem. 1989; 264: 2455-2462Abstract Full Text PDF PubMed Google Scholar, 55Arkhammar P. Juntti-Berggren L. Larsson O. Welsh M. Nanberg E. Sjöholm A. Kohler M. Berggren P.O. J. Biol. Chem. 1994; 269: 2743-2749Abstract Full Text PDF PubMed Google Scholar, 56Velasco J.M. Petersen O.H. Q. J. Exp. Physiol. 1989; 74: 367-370Crossref PubMed Scopus (19) Google Scholar). It has been suggested that the role for PKC is to maintain the phosphorylation state of the voltage-gated l-type Ca2+ channel, thus enabling the appropriate function of this channel (55Arkhammar P. Juntti-Berggren L. Larsson O. Welsh M. Nanberg E. Sjöholm A. Kohler M. Berggren P.O. J. Biol. Chem. 1994; 269: 2743-2749Abstract Full Text PDF PubMed Google Scholar). The resulting effect of TPA is similar but not identical to the effect of KCl because less depolarization is observed in response to TPA and additional actions of TPA have been suggested (35Yada T. Russo L.L. Sharp G.W.G. J. Biol. Chem. 1989; 264: 2455-2462Abstract Full Text PDF PubMed Google Scholar, 55Arkhammar P. Juntti-Berggren L. Larsson O. Welsh M. Nanberg E. Sjöholm A. Kohler M. Berggren P.O. J. Biol. Chem. 1994; 269: 2743-2749Abstract Full Text PDF PubMed Google Scholar). Thus calbindin may be a modulator of insulin secretion in response to both KCl and TPA because both secretagogues act, at least in part, by a similar mechanism. Calbindin, in response to both secretagogues, may act by reducing Ca2+ influx through voltage dependent calcium channels.Although this study clearly establishes for the first time a role for calbindin in the modulation of depolarization-stimulated insulin release (in response to KCl or TPA), the exact role of calbindin in response to other secretagogues (including glucose, a variety of neuropeptides, and other transmitter substances that can combine to activate Ca2+ oscillations in the β cell) remains to be determined. Further studies in βHC cells, which have been reported to preserve the major characteristics of glucose metabolism of native β cells better than other murine β cell lines (22Radvanyi F. Christgau S. Baekkeskov S. Jolicoeur C. Hanahan D. Mol. Cell. Biol. 1993; 13: 4223-4232Crossref PubMed Google Scholar, 57Heimberg H. Devos A. Vandercammen A. Van Schaftingen E. Pipeleers D. Schuit F. Eur. Mol. Biol. Organ. J. 1993; 12: 2873-2879Crossref PubMed Scopus (143) Google Scholar, 58Liang Y. Bai G. Doliba N. Buettger C. Wang L. Berner D.K. Matschinsky F.M. Am. J. Physiol. 1996; 270: E846-E857PubMed Google Scholar), will be of interest to examine the consequences of calbindin overexpression on glucose-dependent functions in the β cells. It is possible that calbindin has a “fine tuning” modulatory role on glucose-dependent insulin release that may not be obvious unless the effect is amplified (for example by activation of protein kinase A).It is also likely that calbindin can have functions in the β cell in addition to modulation of insulin release. Previous studies by Bourlonet al. (59Bourlon P-.M. Faure-Dussert A. Billaudel B. Sutter B.Ch.J. Tramu G. Thomasset M. J. Endocrinol. 1996; 148: 223-232Crossref PubMed Scopus (31) Google Scholar) indicated the presence of calbindin in α as well as β cells of the rat pancreatic islet and suggested an additional role for islet calbindin in glucagon secretion. In this study correlations were made between levels of calbindin as measured by densitometry of immunocytochemically stained sections of pancreas and glucagon secretion. Additional studies using more sensitive methods of quantitation as well as studies with islets from calbindin KO mice may provide additional insight with regard to the interesting possibility of a relationship between calbindin and glucagon secretion. In the nervous system the proposed role of calbindin, similar to its role in the β cell, is to buffer calcium. In the nervous system buffering of calcium by calbindin results in protection against calcium-mediated toxicity. Thus in the β cell, similar to the neuron, in response to depolarization-induced increases in [Ca2+]i, calbindin may buffer the rise in [Ca2+]i to prevent calcium-mediated β cell death. Further studies are needed to examine other potential functions of calbindin in the β cell.The role of calcium targets in the β cell has not been well understood. Although further studies are needed to determine additional mechanisms and multiple consequences of calbindin in the β cell, our findings, using islets from KO mice and β cells lines, are important because they define a role for calbindin in the β cell in calcium regulation and modulation of insulin release. Calbindin-D28k is a 28,000 M rcalcium-binding protein initially identified in avian intestine and was the first known target of vitamin D action (1Wasserman R.H. Taylor A.N. Science. 1966; 152: 791-793Crossref PubMed Scopus (405) Google Scholar). 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 (2Christakos S. Gabrielides C. Rhoten W.B. Endocr. Rev. 1989; 10: 3-26Crossref PubMed Scopus (398) Google Scholar, 3Christakos S. Endocr. Rev. Monograph. 1995; 4: 108-110Google Scholar, 4Christakos S. Beck J.D. Hyllner S.J. Feldman D. Glorieux F. Pike J.W. Vitamin D. Academic Press, San Francisco, CA1997: 209-221Google Scholar). This calcium-binding protein has been conserved during evolution and is regulated by a number of different hormones and factors (3Christakos S. Endocr. Rev. Monograph. 1995; 4: 108-110Google Scholar, 4Christakos S. Beck J.D. Hyllner S.J. Feldman D. Glorieux F. Pike J.W. Vitamin D. Academic Press, San Francisco, CA1997: 209-221Google Scholar). Calbindin-D28k, a predominantly cytosolic protein, is a member of a family of high affinity calcium-binding proteins that includes calmodulin, S100 protein, and parvalbumin (5Heizmann C.W. Hunziker W. Trends Biochem. Sci. 1991; 16: 98-103Abstract Full Text PDF PubMed Scopus (403) Google Scholar). It has been suggested that the role of calbindin in kidney and intestine is to facilitate transcellular calcium diffusion (6Feher J.J. Am. J. Physiol. 1983; 244: C303-C307Crossref PubMed Google Scholar, 7Bronner F. Am. J. Physiol. 1989; 257: F707-F711PubMed Google Scholar). In brain, calbindin is not vitamin D-dependent and its proposed function is to buffer calcium, resulting in protection against calcium-mediated neurotoxicity (8Mattson M.P. Rychlik B. Chu C. Christakos S. Neuron. 1991; 6: 41-51Abstract Full Text PDF PubMed Scopus (485) Google Scholar, 9Guo Q. Christakos S. Robinson N. Mattson M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3227-3232Crossref PubMed Scopus (204) Google Scholar). In 1979 the discovery in the pancreas of a high affinity receptor for the hormonally active form of vitamin D, 1,25- dihydroxyvitamin D3 (1,25(OH)2D3), was the first demonstration of a nonclassical target tissue to contain vitamin D receptors (10Christakos S. Norman A.W. Biochem. Biophys. Res. Commun. 1979; 89: 56-63Crossref PubMed Scopus (105) Google Scholar). Further autoradiographic and immunohistochemical analyses have shown that vitamin D receptors and calbindin-D28k are both localized in the β cell (11Clark S.A. Stumpf W.E. Sar M. DeLuca H.F. Tanaka Y. Cell Tissue Res. 1980; 209: 515-520Crossref PubMed Scopus (119) Google Scholar, 12Roth J. Bonner-Weir S. Norman A.W. Orci L. Endocrinology. 1982; 110: 2216-2218Crossref PubMed Scopus (99) Google Scholar, 13Johnson J.A. Grande J.P. Roche P. Kumar R. Am. J. Phy" @default.
• W2002602258 created "2016-06-24" @default.
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