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PubMed2000

Site-site communication in the EF-hand Ca2+-binding protein calbindin D9k.

The cooperative binding of Ca2+ ions is an essential functional property of the EF-hand family of Ca2+-binding proteins. To understand how these proteins function, it is essential to characterize intermediate binding states in addition to the apo- and holo-proteins. The three-dimensional solution structure and fast time scale internal motional dynamics of the backbone have been determined for the half-saturated state of the N56A mutant of calbindin D9k with Ca2+ bound only in the N-terminal site. The extent of conformational reorganization and a loss of flexibility in the C-terminal EF-hand upon binding of an ion in the N-terminal EF-hand provide clear evidence of the importance of site-site interactions in this family of proteins, and demonstrates the strength of long-range effects in the cooperative EF-hand Ca2+-binding domain.

Allosteric Site↗

PubMed2001

Immunohistochemical localization of calbindin D-28k in the migratory pathway from the rat olfactory placode.

The spatiotemporal localization of calbindin D-28k (Calb), a calcium-binding protein, was examined immunohistochemically in the developing rat olfactory system with special reference to cell migration from the olfactory placode. Calb immunoreactivity was first detected at embryonic day 12 (E12) in a few cells just outside the olfactory epithelium, and at E13, Calb-immunoreactive cells were found scattered in the laminin-rich mesenchyme. By E14, Calb-immunoreactive cells had increased in number and were seen along the entire migratory route between the vomeronasal organ, a derivative of the medial olfactory pit, and the ventromedial surface of the telencephalic vesicle. Calb neurones were not seen in the olfactory epithelium, a derivative of the lateral olfactory pit. Although the distribution pattern of Calb-immunoreactive cells was similar to that of luteinizing hormone releasing hormone (LHRH)-producing neurones, which are known to originate in the vomeronasal organ and migrate into the forebrain, Calb and LHRH immunoreactivities were contained in separate neuronal populations. Calb-immunoreactive cells were localized along the vomeronasal nerves, identified by labelling the vomeronasal organ with the lipophilic dye, DiI, and strongly immunoreactive for neural cell adhesion molecule (NCAM). These data strongly suggest that, in addition to LHRH neurones, the rat vomeronasal organ generates Calb-immunoreactive neurones which migrate along the vomeronasal nerves to enter the forebrain. The final fate and functional importance of these cells remains to be determined.

Animals↗

PubMed2002

Expression of calbindin-D9k messenger ribonucleic acid in the gastrointestinal tract of dairy cattle.

The calcium demands of pregnancy and lactation are known to up-regulate expression of Calbindin-D9k (CaBP-9k) mRNA in the intestines. The gastrointestinal CaBP-9k mRNA expressions has not been studied in dairy cows, which are bound to experience several pregnancies and lactation stages. In this study, the CaBP-9k mRNA expression were examined in the gastrointestinal tract of Holstein dairy cattle by Northern blot analysis. Detectable expression of CaBP-9k mRNA was localized in the proximal portion of the small intestines. These expressions were higher at the most proximal region of the duodenum and gradually decreased distally. The duodenal CaBP-9k mRNA was detected in all dairy cattle from 0.4 to 83.4 months old, but was not detectable in foetuses. There were no significant correlations between the age and the levels of CaBP-9k mRNA expression or between the plasma 1,25-(OH)2D3 concentrations and the levels of CaBP-9k mRNA expression.

Age Factors↗

PubMed1998

Metamorphosis-associated and region-specific expression of calbindin gene in the posterior intestinal epithelium of Xenopus laevis larva.

The present study used a molecular approach toward understanding the mechanism of hormone- and region-dependent remodeling of the small intestine during metamorphosis of Xenopus laevis. A protein spot was noticed on a two-dimensional polyacrylamide gel as a protein whose expression was metamorphic stage- and region-dependent. The protein was identified as the Xenopus homolog (Xcalbindin) of chick calbindin D28k. Xcalbindin expression in the intestine was restricted to absorptive cells in the posterior part, being detectable at stages 49-61, not detectable at stages 62-63, detectable again at stages 64-66, and finally becoming undetectable in the adult. During spontaneous metamorphosis, the level of Xcalbindin mRNA was significantly increased between stages 57 and 58, dramatically reduced at stage 59, and the mRNA was undetectable from stages 60-63, after which it was weakly re-expressed until the end of metamorphosis. Such up- and down-regulation of Xcalbindin mRNA was induced precociously by exogenous thyroid hormone. These results indicated that Xcalbindin is a specific marker of the differentiated absorptive cells of the intestine. Immunohistochemistry with specific antibodies against Xcalbindin demonstrated that precursor cells of adult intestinal epithelial cells expressed Xcalbindin. Considering these results, the origin of adult intestinal epithelial cells was discussed.

Amino Acid Sequence↗

PubMed2000

Alterations in Purkinje cell spines of calbindin D-28 k and parvalbumin knock-out mice.

The second messenger Ca2+ is known to act in a broad spectrum of fundamental cell processes, including modifications of cell shape and motility, through the intermediary of intracellular calcium-binding proteins. The possible impact of the lack of the intracellular soluble Ca2+-binding proteins parvalbumin (PV) and calbindin D-28 k (CB) was tested on spine morphology and topology in Purkinje cell dendrites of genetically modified mice. Three different genotypes were studied, i.e. PV or CB single knock-out (PV-/-, CB-/-) and PV and CB double knock-out mice (PV-/-CB-/-). Purkinje cells were microinjected with Lucifer Yellow and terminal dendrites scanned at high resolution with a confocal laser microscope followed by three-dimensional (3-D) reconstruction. The absence of PV had no significant effect on spine morphology, whereas the absence of CB resulted in a slight increase of various spine parameters, most notably spine length. In double knock-out mice, the absence of both PV and CB entailed a doubling of spine length, an increase in spine volume and spine surface, a higher spine density along the dendrites, as well as a more clustered spine distribution. In all three genotypes, a reduction in the number of stubby spines was observed compared with wild-type animals. These results suggest a morphological compensation for the lack of the soluble calcium buffers in the cytoplasm of Purkinje cell dendritic spines. The increase in various spine parameters, particularly volume, may counteract the lack of the calcium buffers, such as to adjust Ca2+-transients at the transitional zone between spines and dendrites.

Animals↗

PubMed2002

Calbindin neurons in the hamster suprachiasmatic nucleus do not exhibit a circadian variation in spontaneous firing rate.

The role of the mammalian suprachiasmatic nuclei (SCN) in generating circadian rhythms in behaviours and other physiological processes is well established. A prominent feature of SCN neurons is the circadian oscillation in action potential firing frequency, with a peak near midday. A subset of calbindin-immunoreactive (CB+) neurons form a compact subnucleus (CBsn) in the hamster SCN. Restoration of rhythmicity using fetal SCN grafts in SCN-lesioned hamsters is critically dependent upon the presence of CB+ neurons within the transplanted grafts [LeSauter & Silver (1999) J. Neurosci., 5574-5585]. The aim of the current study was to determine whether CB+ neurons within the CBsn of the hamster SCN fire action potentials in a circadian pattern as part of their output signal. Using patch-clamp recording, we demonstrated that CB+ neurons in the CBsn do not express a circadian rhythm in spontaneous firing frequency under diurnal conditions in vitro. Furthermore, the percentage of silent CB- cells varies with zeitgeber time, whereas the percentage of silent CB+ cells does not. Immunohistochemical analysis revealed that the CBsn is a nonhomogeneous nucleus, containing many more CB- than CB+ cells. Our results reveal that CB+ neurons within the CBsn represent a functionally distinct neuronal subpopulation in which rhythmic action potential output may not be necessary for the restoration of behavioural circadian rhythmicity.

Action Potentials↗

PubMed2004

Endometrial calbindins are critical for embryo implantation: evidence from in vivo use of morpholino antisense oligonucleotides.

The endometrium is receptive to embryo implantation only for a short period in each reproductive cycle: development of receptivity requires alterations in endometrial gene expression. Calbindin (CaBP)-d9k and CaBP-d28k are related proteins containing EF hand motifs that have a high affinity for Ca2+. We previously demonstrated that endometrial expression of CaBP-d9k mRNA is highly regulated during implantation in the mouse. This project aimed to determine the temporal and spatial expression of both CaBP proteins during early pregnancy and to establish whether they are necessary for blastocyst implantation. CaBP-d28k protein, like CaBP-d9k, was up-regulated in the endometrial epithelium just before implantation but disappeared at implantation sites after attachment. By the judicious intrauterine injection of morpholino oligonucleotides (MO) against CaBP-d9k into WT and CaBP-d28k null mice just before implantation, we selectively eliminated one or both CaBPs from the uterine epithelium. Implantation was blocked only when both CaBP-d9k and CaBP-d28k were absent: treated WT mice and untreated CaBP-d28k null mice were fertile. Furthermore, the effect on implantation was highly dependent on the timing of injection of MO. This report examining the function of implantation-related genes in the uterus using MO demonstrates that this technique is a highly effective means to specifically target uterine proteins in vivo. This study provides evidence for an absolute requirement for CaBPs during the early phase of embryo implantation, and thus that regulation of Ca2+ availability in the uterine environment of the implanting embryo is critical for successful implantation.

Animals↗

PubMed1987

Calbindin-D in peripheral nerve cells is vitamin D and calcium dependent.

The vitamin D-induced calcium-binding protein calbindin-D (CaBP) was localized immunohistochemically in some but not all of the cell bodies and axons within the intestinalis nerve of the chicken. Unlike other nerve tissue thus far examined, the CaBP content of the intestinalis nerve was decreased in vitamin D deficiency and increased in chicken adapted to a calcium-deficient diet. These changes are qualitatively similar to the pattern of response of enterocytes. The inclusion of calcium-containing solutions within the duodenal lumen caused, directly or indirectly, a decrease in the amount of CaBP in this nerve in a dose-dependent manner. The exact role of CaBP in intestinalis nerve cells is unknown but may be in the regulation of intracellular ionic Ca2+ concentrations during excitation, although other functions of CaBP cannot be excluded.

Animals↗

PubMed1989

Proline isomerism leads to multiple folded conformations of calbindin D9k: direct evidence from two-dimensional 1H NMR spectroscopy.

A complete analysis of calbindin D9k by two-dimensional 1H nuclear magnetic resonance spectroscopy has established the existence of two conformations for the folded protein in solution. Well-resolved major and minor resonances in a ratio of 3:1 are observed throughout the 1H NMR spectrum. Two-dimensional exchange experiments show that the major and minor species are related by an equilibrium process. Analysis of short proton-proton distances along the peptide backbone, identified by two-dimensional nuclear Overhauser effect spectroscopy, provides unambiguous evidence that the two forms of the folded protein differ only in the isomerization state of the peptide bond between Gly-42 and Pro-43. Cis-trans isomerism of Pro-43 is thereby directly identified as the cause of multiple conformations for the folded protein in solution. In addition, when Pro-43 is mutated to a glycine residue there is no indication of multiple conformations. These results provide evidence for the possibility of conformational heterogeneity in the native state of globular proteins.

Calbindins↗

PubMed1999

Energy-based de novo protein folding by conformational space annealing and an off-lattice united-residue force field: application to the 10-55 fragment of staphylococcal protein A and to apo calbindin D9K.

The conformational space annealing (CSA) method for global optimization has been applied to the 10-55 fragment of the B-domain of staphylococcal protein A (protein A) and to a 75-residue protein, apo calbindin D9K (PDB ID code), by using the UNRES off-lattice united-residue force field. Although the potential was not calibrated with these two proteins, the native-like structures were found among the low-energy conformations, without the use of threading or secondary-structure predictions. This is because the CSA method can find many distinct families of low-energy conformations. Starting from random conformations, the CSA method found that there are two families of low-energy conformations for each of the two proteins, the native-like fold and its mirror image. The CSA method converged to the same low-energy folds in all cases studied, as opposed to other optimization methods. It appears that the CSA method with the UNRES force field, which is based on the thermodynamic hypothesis, can be used in prediction of protein structures in real time.

Amino Acid Substitution↗

PubMed1996

Tissue-specific and hormonal regulation of calbindin-D9K fusion genes in transgenic mice.

The rat Calbindin-D9K (CaBP9K) gene is mainly expressed in intestine, uterus, and lung and is regulated in a complex tissue-specific manner. To analyze the role of potential regulatory elements, previously defined by DNaseI hypersensivity, we made transgenic mice containing truncated rat CaBP9K fusion gene with simian virus 40 large T antigen and the chloramphenicol acetyltransferase as reporter genes. The transgenes contained CaBP9K promoter fragments with 5' end points at -4400, -1011, and -117 base pairs (bp), whereas the 3' end points was at +365 bp. Northern blot analysis of T antigen expression and chloramphenicol acetyltransferase enzyme-linked immunosorbent assay indicated that a positive element, probably the distal intestine-specific DNaseI HS, necessary to target the expression of the transgene in the intestine, is present between -4400 and -1011 bp. The cephalo-caudal gradient of expression of the transgene along the small intestine was similar to those of the endogenous gene, but an ectopic expression of the transgene was observed in the colon. The -1011 transgene was expressed in epithelial alveolar cells of the lung, in renal proximal tubule cells, and in uterine myometrium, as judged from immunocytochemical, histological, and Northern blot analyses. The shortest, -117 construct was only expressed in uterine myometrium, and it was under a strict estrogen dependence like the endogenous gene. Finally, responsiveness to vitamin D in the duodenum was observed with the largest, -4400 construct. Thus, different tissues utilize distinct cis-acting elements to direct and regulate the expression of the rat CaBP9K gene.

Animals↗

PubMed1998

Intestinal expression of the calbindin-D9K gene in transgenic mice. Requirement for a Cdx2-binding site in a distal activator region.

The calbindin-D9K gene encodes a vitamin D-induced calcium-binding protein that is expressed as a marker of small intestine differentiation. We have shown that 4580 base pairs of its 5' DNA regulatory region can target reporter transgene expression in the intestine and cause this transgene to respond like the endogenous gene to vitamin D active metabolite and that the homeoprotein Cdx2 is bound to the TATA box in the intestine. We now show that the 4580 base pairs construct confers a differentiated pattern of reporter transgene expression in the intestine and that cooperation between the proximal promoter and a distal element located in an opened chromatin structure is responsible for the intestinal expression and vitamin D responsiveness of the transgene. Gel shift and footprinting assays using duodenal nuclear extracts indicate that this distal element contains a Cdx2-binding site. Finally, a mutation in this distal Cdx2-binding site dramatically decreases intestinal expression in transgenic mice. This report, using an in vivo approach, demonstrates the crucial role of Cdx2 for the transcription of an intestinal gene.

Animals↗

PubMed1998

Effects of age at onset of production, light regime and dietary calcium on performance, eggshell traits, duodenal calbindin and cholecalciferol metabolism.

1. Rate of production and shell thickness (ST) decreased, while body weight (BW), egg weight (EW) and percentage breakage increased progressively with age. Shell weight (SW) increased until 8 to 13 months of age and then decreased. 2. Early onset of production resulted in lower BW and EW at the onset of production, and lower pooled averages of BW, EW, SW and ST, as compared with late or medial onset of production. In 4 out of 5 trials, early onset did not result in the production of more eggs during the laying period. 3. Early onset of production is associated with physiological Ca deficiency as indicated by increases in kidney-1-hydroxylase and duodenal calbindin in early layers as compared with late layers. Early layers exhibited a more severe reduction in shell quality as the result of Ca deficiency as compared with late layers. 4. Feeding pullets with a prelaying diet containing 3.9% Ca did not affect unequivocally the performance or shell quality during the whole productive period, whether the birds started to lay early or late. The dietary treatment did not cause renal damage, as indicated by morphological examination and by plasma calcium and uric acid concentration.

Age Factors↗

PubMed2005

Calbindin distribution in cortical and subcortical brain structures of normal and rabies-infected mice.

Rabies has been an enigmatic disease of the nervous system because microscopic findings in the brain tissue are not paralleled by the severity of the clinical illness. The calcium binding protein calbindin (CB) is a neuronal marker of great interest in neuroanatomy and neuropathology. CB-ir neurons in the striatum and cerebral cortex are gabaergic cells. In the present work CB-immunoreactivity was evaluated in brains of normal and rabies-infected mice. Rabies infection caused loss of CB-immunostaining in the cortical supragranular layers as well as in the striatum. Loss of CB in the brains of mice infected with rabies virus can produce impairment in Ca++ homeostasis and in the gabaergic neurotransmission.

Animals↗

PubMed2006

Calbindin D-28k immunoreactivity increases in the hippocampus after long-term treatment of soy isoflavones in middle-aged ovariectomized and male rats.

This article investigates the long-term effects of soybean isoflavones (ISO) on the changes of calbindin D-28k (CB) immunoreactivity in the hippocampus in middle-aged ovariectomized female rats as well as middle-aged control female and male rats to identify any correlation between calcium and phytoestrogens. In the CA1 region, CB immunoreactivity in the ovariectomized females was similar to that of the control females, whereas CB immunoreactivity in the males was significantly lower than that of the control females. In the dentate gyrus, CB immunoreactivity in the ovariectomized females and males was significantly lower than that of the control females. CB immunoreactivity in all groups was increased dose-dependently after ISO treatment in the CA1 region and dentate gyrus. This result suggests that ISO treatment enhances the expression of CB immunoreactivity in the hippocampus in the middle-aged rats.

Age Factors↗

PubMed1998

Dietary fructooligosaccharides increase calcium absorption and levels of mucosal calbindin-D9k in the large intestine of gastrectomized rats.

BACKGROUND: In gastrectomized rats intestinal calcium absorption and bone calcium levels markedly decrease and the levels recover as a result of feeding fructooligosaccharides (FOS). In the present study we examined the effects of gastrectomy and dietary FOS on intestinal calbindin-D9k (CaBP) levels. METHODS: One group of rats was subjected to a sham operation and fed a control diet. Two other groups of rats were gastrectomized, and those in one group were fed the control diet, whereas those in the other group were fed a diet containing 10% FOS. Intestinal calcium, magnesium, and phosphorus absorption levels and intestinal CaBP levels were measured. RESULTS: Gastrectomy increased CaBP levels in the distal small intestine, cecum, and colorectum but markedly decreased calcium absorption. Dietary FOS increased CaBP levels in the cecum and colorectum in the case of gastrectomized rats and improved calcium absorption. CONCLUSIONS: The results suggest that dietary FOS not only improve intestinal calcium absorption but also serve to maintain local calcium homeostasis in the intestine by increasing mucosal CaBP levels in the large intestine of gastrectomized rats.

Animals↗

PubMed2004

The role of mitochondrial alterations in the combined toxic effects of human immunodeficiency virus Tat protein and methamphetamine on calbindin positive-neurons.

The use of methamphetamine (METH) continues to increase the risk of human immunodeficiency virus (HIV) transmission within both homosexual and heterosexual drug abuser groups. Neurological studies indicate that the progression of HIV encephalitis is also enhanced by illicit drug use. Recently, the authors' studies in the postmortem brains of HIV-positive METH users have shown that the combined effects of HIV and METH selectively damage calbindin (CB)-immunoreactive nonpyramidal neurons, which may contribute to the behavioral alterations observed in these patients. To better understand the mechanisms of toxicity associated with exposure to HIV and METH, neuronal survival, phenotypic markers, levels of oxidative stress, and mitochondrial potential were assessed in vitro in the hippocampal neuronal cell line, HT22, and in primary human neurons exposed to the HIV Tat protein and/or METH. Both Tat and METH were toxic to neurons in a time- and dose-dependent fashion. Neurons exposed to a combination of Tat and METH displayed early evidence of neuronal damage at 6 h, characterized by a decrease in CB and microtubule-associated protein 2 (MAP2) immunoreactivity followed by more extensive cell death at 24 h. Loss of CB immunoreactivity associated with the combined exposure to Tat and METH was accompanied by mitochondrial damage with increased levels of oxidative stress. The toxic effects of Tat and METH were inhibited by blocking mitochondrial uptake of intracellular calcium, whereas blocking calcium flux in the endoplasmic reticulum or from the extracellular environment had no effect on Tat and METH toxicity. These studies indicate that in vitro, when combined, the HIV protein Tat and METH damage CB-immunoreactive nonpyramidal neurons by dysregulating the mitochondrial calcium potential. In combination, Tat and METH may increase cell injury and death, thereby enhancing brain metabolic disturbances observed in HIV-positive METH users in clinical populations.

Animals↗

PubMed2002

'New' functions for 'old' proteins: the role of the calcium-binding proteins calbindin D-28k, calretinin and parvalbumin, in cerebellar physiology. Studies with knockout mice.

Calretinin (CR), calbindin D-28k (CB) and parvalbumin (PV) belong to the large family of EF-hand calcium-binding proteins, which comprises more than 200 members in man. Structurally these proteins are characterized by the presence of a variable number of evolutionary well-conserved helix-loop-helix motives, which bind Ca2+ ions with high affinity. Functionally, they fall into two groups: by interaction with target proteins, calcium sensors translate calcium concentrations into signaling cascades, whereas calcium buffers are thought to modify the spatiotemporal aspects of calcium transients. Although CR, CB and PV are currently being considered calcium buffers, this may change as we learn more about their biology. Remarkable differences in their biophysical properties have led to the distinction of fast and slow buffers and suggested functional specificity of individual calcium buffers. Evaluation of the physiological roles of CR, CB and PV has been facilitated by the recent generation of mouse strains deficient in these proteins. Here, we review the biology of these calcium-binding proteins with distinct reference to the cerebellum, since they are particularly enriched in specific cerebellar neurons. CR is principally expressed in granule cells and their parallel fibres, while PV and CB are present throughout the axon, soma, dendrites and spines of Purkinje cells. PV is additionally found in a subpopulation of inhibitory interneurons, the stellate and basket cells. Studies on deficient mice together with in vitro work and their unique cell type-specific distribution in the cerebellum suggest that these calcium-binding proteins have evolved as functionally distinct, physiologically relevant modulators of intracellular calcium transients. Analysis of different brain regions suggests that these proteins are involved in regulating calcium pools critical for synaptic plasticity. Surprisingly, a major role of any of these three calcium-binding proteins as an endogenous neuroprotectant is not generally supported.

Animals↗