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PubMed2003

m-Calpain colocalizes with the calcium-sensing receptor (CaR) in caveolae in parathyroid cells and participates in degradation of the CaR.

The calcium-sensing receptor (CaR) is a G protein-coupled, seven-transmembrane receptor and resides within caveolin-rich membrane domains in bovine parathyroid cells. The proenzyme of calpain 2 (m-calpain) is a heterodimeric calcium-dependent cysteine protease consisting of catalytic and regulatory subunits. The effects of calcium on the enzyme include activation, autolysis, and subunit dissociation. Here, we examine the potential role of caveolin-1 and caveolae in regulating the cellular distribution and function of m-calpain in parathyroid cells. We show that the inactive heterodimeric forms of m-calpain are concentrated in caveolin-rich membrane fractions prepared from parathyroid cells incubated with low extracellular calcium (Ca2+(o)). In contrast, in cells incubated with 3 mm Ca2+(o), which activates the CaR and increases intracellular calcium, there is a reduction in m-calpain in association with an increase in CaR protein and phosphorylated protein kinase C alpha and beta in caveolin-rich fractions. To assess the impact of activation of calpain on CaR protein in caveolar fractions, we analyzed the effects of m-calpain on the CaR. Activation of the CaR with high Ca2+(o) induced the release of lower molecular weight fragments of the receptor into the cell culture medium, and calpain inhibitors blocked this effect. Moreover, the fragments of the CaR as well as caveolin-1, m-calpain, and alkaline phosphatase were localized in membrane vesicles shed by parathyroid cells, supporting the association of these proteins in living cells. Treatment of CaR proteins in vitro with m-calpain also resulted in the appearance of lower molecular weight fragments of the CaR. Our data suggest that localization of m-calpain within caveolae may contribute to maintenance of the enzyme in an inactive state and that m-calpain may also contribute to the regulation of CaR levels.

Animals↗
PubMed2000

Extracellular calcium-sensing-receptor (CaR)-mediated opening of an outward K(+) channel in murine MC3T3-E1 osteoblastic cells: evidence for expression of a functional CaR.

The existence in osteoblasts of the G-protein-coupled extracellular calcium (Ca(o)(2+))-sensing receptor (CaR) that was originally cloned from parathyroid and kidney remains controversial. In our recent studies, we utilized multiple detection methods to demonstrate the expression of CaR transcripts and protein in several osteoblastic cell lines, including murine MC3T3-E1 cells. Although we and others have shown that high Ca(o)(2+) and other polycationic CaR agonists modulate the function of MC3T3-E1 cells, none of these actions has been unequivocally shown to be mediated by the CaR. Previous investigations using neurons and lens epithelial cells have shown that activation of the CaR stimulates Ca(2+)-activated K(+) channels. Because osteoblastic cells express a similar type of channel, we have examined the effects of specific "calcimimetic" CaR activators on the activity of a Ca(2+)-activated K(+) channel in MC3T3-E1 cells as a way of showing that the CaR is not only expressed in those cells but is functionally active. Patch-clamp analysis in the cell-attached mode showed that raising Ca(o)(2+) from 0.75 to 2.75 mmol/L elicited about a fourfold increase in the open state probability (P(o)) of an outward K(+) channel with a conductance of approximately 92 pS. The selective calcimimetic CaR activator, NPS R-467 (0.5 micromol/L), evoked a similar activation of the channel, while its less active stereoisomer, NPSS-467 (0.5 micromol/L), did not. Thus, the CaR is not only expressed in MC3T3-E1 cells, but is also functionally coupled to the activity of a Ca(2+)-activated K(+) channel. This receptor, therefore, could transduce local or systemic changes in Ca(o)(2+) into changes in the activity of this ion channel and related physiological processes in these and perhaps other osteoblastic cells.

Animals↗
PubMed2003

Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes.

The orphan nuclear constitutive androstane receptor (CAR) is proposed to play a central role in the response to xenochemical stress. Identification of CAR target genes in humans has been limited by the lack of a selective CAR agonist. We report the identification of 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO) as a novel human CAR agonist with the following characteristics: (a) potent activity in an in vitro fluorescence-based CAR activation assay; (b) selectivity for CAR over other nuclear receptors, including the xenobiotic pregnane X receptor (PXR); (c) the ability to induce human CAR nuclear translocation; and (d) the ability to induce the prototypical CAR target gene CYP2B6 in primary human hepatocytes. Using primary cultures of human hepatocytes, the effects of CITCO on gene expression were compared with those of the PXR ligand rifampicin. The relative expression of a number of genes encoding proteins involved in various aspects of steroid and xenobiotic metabolism was analyzed. Notably, CAR and PXR activators differentially regulated the expression of several genes, demonstrating that these two nuclear receptors subserve overlapping but distinct biological functions in human hepatocytes.

Cells, Cultured↗
PubMed2006

Why do red and dark-coloured cars lure aquatic insects? The attraction of water insects to car paintwork explained by reflection-polarization signals.

We reveal here the visual ecological reasons for the phenomenon that aquatic insects often land on red, black and dark-coloured cars. Monitoring the numbers of aquatic beetles and bugs attracted to shiny black, white, red and yellow horizontal plastic sheets, we found that red and black reflectors are equally highly attractive to water insects, while yellow and white reflectors are unattractive. The reflection-polarization patterns of black, white, red and yellow cars were measured in the red, green and blue parts of the spectrum. In the blue and green, the degree of linear polarization p of light reflected from red and black cars is high and the direction of polarization of light reflected from red and black car roofs, bonnets and boots is nearly horizontal. Thus, the horizontal surfaces of red and black cars are highly attractive to red-blind polarotactic water insects. The p of light reflected from the horizontal surfaces of yellow and white cars is low and its direction of polarization is usually not horizontal. Consequently, yellow and white cars are unattractive to polarotactic water insects. The visual deception of aquatic insects by cars can be explained solely by the reflection-polarizational characteristics of the car paintwork.

Animals↗
PubMed1998

Dimerization of the extracellular calcium-sensing receptor (CaR) on the cell surface of CaR-transfected HEK293 cells.

The extracellular calcium (Ca2+o)-sensing receptor (CaR) is a G protein-coupled receptor that plays important roles in calcium homeostasis. In this study, we employed epitope tagging, cell-surface biotinylation, and immunoprecipitation techniques to demonstrate that the CaR is expressed mostly in the form of a dimer on the surface of transfected human embryonic kidney (HEK293) cells. Western analysis of cell-surface proteins under nonreducing conditions showed that the CaR exists in several forms with molecular masses greater than 200 kDa. Most of these high molecular mass forms of the receptor could be converted to a single monomeric species at 160 kDa under reducing conditions. This result suggests that the CaR forms dimers or even higher oligomers on the cell surface through intermolecular disulfide bonds that are sensitive to reducing agents. Consistent with this hypothesis, use of a cell-surface cross-linking agent substantially increases the proportion of the putative dimeric CaR at 280 kDa relative to the monomeric form of the receptor at 160 kDa under reducing conditions. Dimerization of the CaR in intact cells was further demonstrated when we co-transfected and co-immunoprecipitated the wild type, full-length receptor and a truncated form of the CaR lacking its cytoplasmic tail. Taken together, we conclude from these results that the functional CaR resides on the cell surface of transfected HEK293 cells in the form of a dimer.

Biotinylation↗
PubMed2001

Adenovirus type 9 fiber knob binds to the coxsackie B virus-adenovirus receptor (CAR) with lower affinity than fiber knobs of other CAR-binding adenovirus serotypes.

The coxsackie B virus and adenovirus (Ad) receptor (CAR) functions as an attachment receptor for multiple Ad serotypes. Here we show that the Ad serotype 9 (Ad9) fiber knob binds to CAR with much reduced affinity compared to the binding by Ad5 and Ad12 fiber knobs as well as the knob of the long fiber of Ad41 (Ad41L). Substitution of Asp222 in Ad9 fiber knob with a lysine that is conserved in Ad5, Ad12, and Ad41L substantially improved Ad9 fiber knob binding to CAR, while the corresponding substitution in Ad5 (Lys442Asp) significantly reduced Ad5 binding. The presence of an aspartic acid residue in Ad9 therefore accounts, at least in part, for the reduced CAR binding affinity of the Ad9 fiber knob. Site-directed mutagenesis of CAR revealed that CAR residues Leu73 and Lys121 and/or Lys123 are critical contact residues, with Tyr80 and Tyr83 being peripherally involved in the binding interaction with the Ad5, Ad9, Ad12, and Ad41L fiber knobs. The overall affinities and the association and dissociation rate constants for wild-type CAR as well as Tyr80 and Tyr83 CAR mutants differed between the serotypes, indicating that their binding modes, although similar, are not identical.

Adenoviruses, Human↗
PubMed2001

Use of seat belts in cars with different seat belt reminder systems. A study of injured car drivers.

The use of seat belts in cars with different seat belt reminder systems was analyzed in a population of 477 injured car drivers, transported by ambulance to Umeå University Hospital after car crashes. The ambulance personnel acted as independent observers regarding the use of seat belts. In this population the non-users were significantly (multivariate logistic regression) fewer (12%) in cars with a combined light and sound reminder, compared to cars without reminder (23%). In cars with only a light signal the proportion of non-users was the same as in cars without any reminder at all. An introduction of more effective reminders, at least in new cars, might be an effective way to increase seat belt usage rates in the long-term.

Accidents, Traffic↗
PubMed1994

Comparison of 7,12-dimethylbenz(a)anthracene-DNA adduction in the epidermis of two lines of mice selected for resistance (CAR-R) or susceptibility (CAR-S) to skin carcinogenesis.

Two lines of mice were produced by bidirectional selective breeding: one resistant (CAR-R) and one susceptible (CAR-S) to two-stage skin carcinogenesis by dimethylbenz(a)anthracene and 12-O-tetradecanoyl-phorbol-13-acetate. The dimethylbenz(a)anthracene-DNA adduct formation was compared in the two lines by a postlabeling procedure so as to determine whether the striking interline difference observed as to tumor incidence could (in part) be due to differences in the formation of DNA-reactive metabolites. Results show that qualitatively, adduct profiles in CAR-R and CAR-S epidermis are similar. Quantitatively, the total binding level is slightly higher in CAR-S versus CAR-R mice during the 30-day follow-up. However, these minor differences do not increase in function of the response to selection observed through three consecutive generations. A 2- or 4-week promotion with 12-O-tetradecanoylphorbol-13-acetate enhances the decrease of adduct level in the two lines. This effect is somewhat more pronounced in CAR-S mice. Results strongly suggest that the expression of the genes responsible for CAR-R/CAR-S phenotypic difference affects mainly the postinitiation stages.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2003

Car insurance and the risk of car crash injury.

Despite speculation about the role of vehicle insurance in road traffic accidents, there is little research estimating the direction or extent of the risk relationship. Data from the Auckland Car Crash Injury Study (1998-1999) were used to examine the association between driving an uninsured motor vehicle and car crash injury. Cases were all cars involved in crashes in which at least one occupant was hospitalized or killed anywhere in the Auckland region. Controls were 588 drivers of randomly selected cars on Auckland roads. Participants completed a structured interview. Uninsured drivers had significantly greater odds of car crash injury compared to insured drivers after adjustment for age, sex, level of education, and driving exposure (odds ratio 4.77, 95% confidence interval 2.94-7.75). The causal mechanism for insurance and car crash injury is not easily determined. Although we examined the effects of multiple potential confounders in our analysis including socioeconomic status and risk-taking behaviours, both of which have been previously observed to be associated with both insurance status and car crash injury, residual confounding may partly explain this association. The estimated proportion of drivers who are uninsured is between 5 and 15% in developed countries, representing a significant public health problem worthy of further investigation.

Accidents, Traffic↗
PubMed1997

Cao-sensing receptor (CaR)-mediated activation of K+ channels is blunted in CaR gene-deficient mouse neurons.

The extracellular Ca2+ (Cao)-sensing receptor (CaR) is expressed in hippocampus and other brain regions, suggesting that it could mediate some of the well recognized but poorly understood direct actions of Cao on neuronal function. This study presents evidence that the CaR is functionally coupled to Ca(2+)-activated K+ channels. The effects of CaR agonists on these channels in neurons from wild type (WT) and CaR-deficient (CaR -/-) mice were compared. Neomycin (100 mM) and elevation of Cao from 0.5 to 3 mM significantly increased the probability of channel opening (Po) in neurons from WT but not in those from CaR -/- mice. Thus the CaR activates neuronal K+ channels and could potentially inhibit neuronal excitability and neurotransmission via membrane repolarization.

Animals↗
PubMed2006

Car backlight position and fog density bias observer-car distance estimates and time-to-collision judgments.

OBJECTIVE: A series of experiments assessed biases in perceived distance that occur while driving as a function of the backlight position of the car ahead and fog density. BACKGROUND: V. Cavallo, M. Colomb, and J. Doré (2001) have shown that smaller horizontal backlight separation and fog may result in increased estimates of the distance between an observer and a car of which only the backlights are visible. They also predicted that raising the height of the car backlights would lead to increasing distance estimates. METHOD: Distance perception was assessed in both static and dynamic computer-simulated scenarios in which the distance estimates were performed using a familiarized analog scale or using time-to-collision judgments for both pairs of backlights and single backlights. RESULTS: In a series of five experiments, the horizontal separation and fog density effects were replicated. In addition, distance estimates were consistently larger with higher than with lower vertical backlight positions. CONCLUSION: There is reason to believe that biases in distance perception may be augmented by car backlight positions and by low-visibility weather conditions. APPLICATION: Car designers should take backlight placement seriously. Speed-dependent car-to-car distance control systems seem desirable to counteract biases in distance perception.

Accidents, Traffic↗
PubMed2001

Factors influencing the patterns of injuries and outcomes in car versus car crashes compared to sport utility, van, or pick-up truck versus car crashes: Crash Injury Research Engineering Network Study.

BACKGROUND: Data using crash dummies suggest that motor vehicle crashes (MVCs) involving passenger sedans (S) vs sport utility, vans, or light trucks (SUVTs) produce more severe injuries than those involving two sedans (SvS). However, no detailed data regarding pattern of injuries or force mechanisms involved have been presented in real patients. METHODS: The relationship of injury patterns and severities with MVC reconstruction data were obtained in 412 MVC patients, drivers or front seat passengers. Crashes were examined with regard to impact direction, frontal (F) or lateral (L) crashes, vehicle mass ratio, ISS, DELTA V, seat belt use, and airbag deployment (AB). RESULTS: In 309 F-MVC, AB reduced overall ISS (24.3 to 17.9) with a reduction in the mean severity of traumatic brain injury (TBI) GCS < or = 12, from 48% to only 28%. This AB protection from TBI was preserved as DELTA V increased to > 30 mph even though non-AB protected body areas (thorax, lung, liver, and lower extremity injuries) all increased. When vehicles of incompatible size and mass (SUVT) had F-MVC with sedans the incidence of severe TBI rose as did face lacerations despite AB or belt use. In L-MVC between SUVT and sedans compared with SvS MVC, there was a cephalad shift in body injuries with increased thorax, but decreased lower extremity injuries. The incidence of TBI increased. Analysis of injury contact sites (hits) showed more hits and a wider distribution of contract sites in SUVT vs sedan MVC. These appeared due to the greater mass excess and larger mass ratio, hood height, and width in the F-SUVT vs S crashes. All of these factors plus the increased bumper height above the body frame side-door sill were injury causal factors in the L-SUVT vs S MVCs. CONCLUSION: Both F and L crashes between sedans and SUVT with a high mass ratio shift the pattern of injury cephalad with increased thorax and intrathoracic organ injuries, and more severe TBI. These data suggest that improved head and thorax side-impact buffering and design features which transmit MVC forces from the higher front end of the larger mass SUVT to the frame of the sedan may better protect sedan occupants from side-impacts.

Accidents, Traffic↗
PubMed1976

Evolution of mammalian carbonic anhydrase loci by tanden duplication: close linkage of Car-1 and Car-2 to the centromere region of chromosome 3 of the mouse.

Electrophoretic variants of two carbonic anhydrase enzymes CAR-1 (CA I) and Car-2 (CA II), have been found in the laboratory mouse, Mus musculus. These two loci are closely linked to each other and are located on chromosome 3 near its centromere. The close linkage of Car-1 and Car-2 supports the hypothesis that the present-day carbonic anhydrase loci are the result of tandem duplication of an earlier carbonic anhydrase locus with subsequent divergence. The red blood cells of mice of the subspecies M.m. casteneus have significantly reduced levels of CAR-1 and CAR-2.

Alleles↗
PubMed1998

Inversion of genetic predisposition to carcinogenesis in liver of two lines of mice selected for resistance (Car-R) or susceptibility (Car-S) to skin carcinogenesis.

Two lines of mice, one resistant (Car-R) and one susceptible (Car-S) to skin carcinogenesis, were produced by bi-directional selective breeding. To see whether the characteristics of susceptibility or resistance to tumorigenesis were also expressed in the liver and lung, the two lines were submitted comparatively to treatment with 5,9-dimethyl dibenzo[c,g]carbazole (DiMeDBC), a potent hepatocarcinogenic derivative of the ubiquitous heterocyclic carcinogenic pollutant, 7H-dibenzo[c,g]-carbazole (DBC). An inversion of genetic predisposition to carcinogenesis in liver was observed. Car-R animals displayed rapid tumorigenesis in 100% of cases while Car-S mice were remarkably less sensitive, showing a 4-fold lower mean tumor multiplicity and a 4-month longer latency time. In parallel adduct formation by DiMeDBC and DBC in liver DNA was analyzed by the 32P-postlabeling method, showing a remarkably higher level in Car-R mice than in Car-S animals. These data indicate that tissue-specific sensibility in carcinogenesis may involve gene expression at various levels.

Animals↗
PubMed2003

Two Italian kindreds with familial hypocalciuric hypercalcaemia caused by loss-of-function mutations in the calcium-sensing receptor (CaR) gene: functional characterization of a novel CaR missense mutation.

OBJECTIVES: Description of two unrelated Italian kindreds with familial hypocalciuric hypercalcaemia (FHH), an autosomal dominant disease mostly caused by heterozygous inactivating mutations of the Ca2+ sensing receptor (CaR). PATIENTS AND DESIGN: We studied 11 members of the two families. Genomic DNA was isolated from peripheral blood leucocytes in all family members and in 50 unrelated Italian controls. Total serum and ionized calcium, PTH, creatinine, phosphate, magnesium, and urinary calcium clearance to creatinine clearance ratio were measured. Direct sequencing of the entire coding region of the CaR was performed in the probands. Functional studies were performed in COS-7 cells transiently expressing the mutated CaR. RESULTS: In the proband of family A direct sequencing revealed a novel heterozygous Y218C missense mutation in exon 4. The same mutation was identified in the affected but not in the unaffected family members or in any of the 50 unrelated Italian controls. Transient expression of the Y218C CaR in COS-7 cells revealed a blunted Ca2+-evoked accumulation of inositol trisphosphates, indicating that the Y218C is a loss-of-function mutation. Cotransfection experiments showed that the mutant receptor had no impact on the function of the wild-type receptor, suggesting that a reduced expression of the normal CaR, rather than a dominant-negative effect, accounted for the functional impairment. In the proband of family B an already described heterozygous P55L missense mutation in exon 2 of the CaR gene was found. The same mutation was identified in the affected family members. CONCLUSIONS: We described two familial hypocalciuric hypercalcaemia kindreds with loss-of-function mutations of the Ca2+ receptor gene and identified a novel heterozygous mutation (Y218C) characterized by a blunted response to Ca2+ stimulation compared to the wild-type receptor and no interference with the function of the wild-type Ca2+ receptor.

Adult↗
PubMed2003

Does periodic vehicle inspection reduce car crash injury? Evidence from the Auckland Car Crash Injury Study.

OBJECTIVES: This paper examines the association between periodic motor vehicle inspection and frequent tire pressure checks, and the risk of car crash injury. METHODS: Data were analysed from the Auckland Car Crash Injury Study, a population-based case-control study in Auckland, NZ, where vehicles are required to undergo six-monthly safety inspections. Cases were all cars involved in crashes in which at least one occupant was hospitalised or killed, which represented 571 drivers. Controls were randomly selected cars on Auckland roads (588 drivers). Participants completed a structured interview. RESULTS: Vehicles that did not have a current certificate of inspection had significantly greater odds of being involved in a crash where someone was injured or killed compared with cars that had a current certificate, after adjustment for age, sex, marijuana use, ethnicity and licence type (OR 3.08, 95% CI 1.87-5.05). Vehicles that had not had their tire pressure checked within the past three months also had significantly greater odds of being involved in a crash compared with those that had a tire pressure check, after adjustment for age, sex, ethnicity, seatbelt use, licence type, self-reported speed and hours per week of driving exposure (OR 1.89, 95% CI 1.16-3.08). CONCLUSIONS: This study provides new evidence, using rigorous epidemiological methods and controlling for multiple confounding variables, of an association between periodic vehicle inspections and three-monthly tire pressure checks and reduced risk of car crash injury. DISCUSSION: This research suggests that vehicle inspection programs should be continued where they already exist and contributes evidence in support of introducing such programs to other areas.

Accidents, Traffic↗
PubMed1997

Car transportation conditions of preschool children: use of children's car safety seats.

The objective of this study was to evaluate children's car safety seat usage in a non-random study population of the Capital and surrounding area of Attica and a provincial region in Greece. One or both of the parents of 1556 children (aged 0-4 years) were interviewed. A questionnaire covering car safety seat usage by area of residence, age of parents, educational background, socioeconomic status and the number of siblings was completed. Optimal car safety seat restraint usage in the Attica region was 10.4% for infants 0-6 months old, 37.6% for infants 7-12 months old, 40.9% for children aged 1-2 years and 12% for children aged 3-4 years; the use of restraint systems in the provincial area was even lower at 4.9%, 15.2%, 24% and 6.6%, respectively. The mother's age, number of children and the socioeconomic status of the family seemed to influence the purchase and usage of the car safety seat. Such a high percentage of non-usage of car safety restraint seats has led to the Paediatric Society's initiative to create informative general public educational programmes and to urge governmental legislation regarding mandatory usage of children's car safety seats.

Age Factors↗
PubMed2004

Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR.

The constitutive androstane receptor (CAR, NR1I3) is a key regulator of xenobiotic and endobiotic metabolism. The ligand-binding domains of murine (m) and human (h) CAR are divergent relative to other nuclear hormone receptors, resulting in species-specific differences in xenobiotic responses. Here we identify the widely used antiemetic meclizine (Antivert; Bonine) as both an agonist ligand for mCAR and an inverse agonist for hCAR. Meclizine increases mCAR transactivation in a dose-dependent manner. Like the mCAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, meclizine stimulates binding of steroid receptor coactivator 1 to the murine receptor in vitro. Meclizine administration to mice increases expression of CAR target genes in a CAR-dependent manner. In contrast, meclizine suppresses hCAR transactivation and inhibits the phenobarbital-induced expression of the CAR target genes, cytochrome p450 monooxygenase (CYP)2B10, CYP3A11, and CYP1A2, in primary hepatocytes derived from mice expressing hCAR, but not mCAR. The inhibitory effect of meclizine also suppresses acetaminophen-induced liver toxicity in humanized CAR mice. These results demonstrate that a single compound can induce opposite xenobiotic responses via orthologous receptors in rodents and humans.

Animals↗