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Fabiano A.,University of Genoa | Panfoli I.,University of Genoa | Calzia D.,University of Genoa | Bruschi M.,Laboratory on Pathophysiology | And 5 more authors.
Visual Neuroscience | Year: 2011

Cyclic ADP-ribose (cADPR) is a second messenger modulating intracellular calcium levels. We have previously described a cADPR-dependent calcium signaling pathway in bovine rod outer segments (ROS), where calcium ions play a pivotal role. ROS ADP-ribosyl cyclase (ADPR-cyclase) was localized in the membrane fraction. In the present work, we examined the properties of the disk ADPR-cyclase through the production of cyclic GDP-ribose from the NAD + analogue NGD+. The enzyme displayed an estimated Km for NGD+ of 12.5 ± 0.3 μM, a Vmax of 26.50 ± 0.70 pmol cyclic GDP-ribose synthesized/min/mg, and optimal pH of 6.5. The effect of divalent cations (Zn2+, Cu2+, and Ca2+) was also tested. Micromolar Zn2+ and Cu2+ inhibited the disk ADPR-cyclase activity (half maximal inhibitory concentration, IC50 = 1.1 and 3.6 μM, respectively). By contrast, Ca2+ ions had no effect. Interestingly, the properties of the intracellular membrane-associated ROS disk ADPR-cyclase are more similar to those of the ADPR-cyclase found in CD38-deficient mouse brain, than to those of CD38 or CD157. The novel intracellular mammalian ADPR-cyclase would elicit Ca2+ release from the disks at various rates in response to change in free Ca2+ concentrations, caused by light versus dark adaptation, in fact there was no difference in disk ADPR-cyclase activity in light or dark conditions. Data suggest that disk ADPR-cyclase may be a potential target of retinal toxicity of Zn2+ and may shed light to the role of Cu2+ and Zn 2+ deficiency in retina. © 2011 Cambridge University Press. Source

Gharavi A.G.,Columbia University | Kiryluk K.,Columbia University | Choi M.,Howard Hughes Medical Institute | Li Y.,Columbia University | And 51 more authors.
Nature Genetics | Year: 2011

We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance (P values for association between 1.59 -10'26 and 4.84-10'9 and minor allele odds ratios of 0.63-0.80). These five loci explain 4-7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures. © 2011 Nature America, Inc. All rights reserved. Source

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