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Excessive activation of cyclic nucleotide-gated channels contributes to neuronal degeneration of photoreceptors (2005)

Vallazza-Deschamps, Géraldine ; Cia, David ; Gong, Jie ; [et al.]

Oxford, UK : Blackwell Science Ltd

European journal of neuroscience 22 (2005), S. 0

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ISSN: 1460-9568

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: In different animal models, photoreceptor degeneration was correlated to an abnormal increase in cGMP concentration. The cGMP-induced photoreceptor toxicity was demonstrated by applying the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine on retinal explants. To assess the role of cGMP-gated channels in this cGMP toxicity, the Ca2+ channel blockers verapamil and l- and d-diltiazem, which block cGMP-gated channels with different efficacies, were applied to in vitro animal models of photoreceptor degeneration. These models included: (i) adult rat retinal explants incubated with zaprinast, a more specific inhibitor of the rod phosphodiesterase than 3-isobutyl-1-methylxanthine and (ii) rd mouse retinal explants. Photoreceptor apoptosis was assessed by terminal dUTP nick end labelling and caspase 3 activation. Effects of the blockers on the synaptic rod Ca2+ channels were measured by patch-clamp recording. In the zaprinast-induced photoreceptor degeneration model, both diltiazem isomers rescued photoreceptors whereas verapamil had no influence. Their neuroprotective efficacy was correlated to their inhibition of cGMP-gated channels (l-diltiazem 〉 d-diltiazem 〉 verapamil = 0). In contrast, all three Ca2+ channel blockers suppressed rod Ca2+ channel currents similarly. This suppression of the currents by the diltiazem isomers was very weak (16.5%) at the neuroprotective concentration (10 µm). In rd retinal explants, both diltiazem isomers also slowed down rod degeneration in contrast to verapamil. l-diltiazem exhibited this effect at concentrations ranging from 1 to 20 µm. This study further supports the photoreceptor neuroprotection by diltiazem particularly in the rd mouse retina, whereas the absence of neuroprotection by verapamil further suggests the role of cGMP-gated channel activation in the induction of photoreceptor degeneration.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1111/j.1460-9568.2005.04306.x

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Structural and biochemical properties of kinesin heavy chain associated with rat brain mitochondria (1994)

Jellali, Abdeljelil ; Metz-Boutigue, Marie-Hélène ; Surgucheva, Irina ; [et al.]

New York, NY : Wiley-Blackwell

Cell Motility and the Cytoskeleton 28 (1994), S. 79-93

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ISSN: 0886-1544

Keywords: kinesin ; brain mitochondria ; motility ; membrane-associated ; Life and Medical Sciences ; Cell & Developmental Biology

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Biology , Medicine

Notes: Kinesin, a mechanochemical enzyme that translocates membranous organelles, was initially identified and purified from soluble extracts from vertebrate brains. However, immunocytochemical and morphological approaches have demonstrated that kinesin could be associated to intracellular membranous organelles. We used an antibody raised against the head portion of the Drosophila kinesin heavy chain to reveal the presence of this protein in membranous organelles from rat brain. By using differential centrifugation and immunoblotting we observed a 116 kDa protein that crossreacts with this antibody in microsomes, synaptic vesicles, and mitochondria. This protein could be extracted from mitochondria with low salt concentrations or ATP. The 116 kDa solubilized protein has been identified as conventional kinesin based on limited sequence analysis. We also show that a polyclonal antibody raised against mitochondria-associated kinesin recognizes soluble bovine brain kinesin. The soluble and mitochondrial membrane-associated kinesins show a different isoform pattern. These results are consistent with the idea that kinesin exists as multiple isoforms that might be differentially distributed within the cell. In addition digitonin fractionation of mitochondria combined with KI extraction revealed that kinesin is a peripheral protein, preferentially located in a cholesterol-free outer membrane domain; this domain has the features of contact points between the mitochondrial outer and inner membranes. The significance of these observations on the functional regulation of the mitochondria-associated kinesin is discussed. © 1994 Wiley-Liss, Inc.

Additional Material: 9 Ill.