P neurotoxins

EVOLUTIONARY RELATIONSHIPS OF p-NEUROTOXINS CROTOXIN CA CAN INTERFERE WITH SINGLE CHAIN p-NEUROTOXINS FROM VIPERIDAE VENOMS AND MODIFY THEIR PHYSIOLOGICAL PROPERTIES... 

From an ecotoxicological point of view, it has often been suspected that sublethal effects, such as those described here, can be more important than lethal ones. Both p,p -DDT and p,p -DDD are persistent neurotoxins, and may very well have caused behavioral effects in the field. This issue was not resolved when DDT was widely used, and remains a matter for speculation. More is known, however, about eggshell thinning caused by p,p -DDE and its effects upon reproduction, which will be discussed in Section 5.2.5.I. 

Oberdorster, E. and McClellan-Green, P. (2002). Mechanisms of imposex induction in the mud snail, Ilyanassa obsoleta TBT as a neurotoxin and aromatase inhibitor. Marine Environmental Research 54, 715-718. 

Research in this area advanced in the 1970 s as several groups reported the isolation of potent toxins from P. brevis cell cultures (2-7). To date, the structures of at least eight active neurotoxins have been elucidated (PbTx-1 through PbTx-8) (8). Early studies of toxic fractions indicated diverse pathophysiological effects in vivo as well as in a number of nerve and muscle tissue preparations (reviewed in 9-11). The site of action of two major brevetoxins, PbTx-2 and PbTx-3, has been shown to be the voltage-sensitive sodium channel (8,12). These compounds bind to a specific receptor site on the channel complex where they cause persistent activation, increased Na flux, and subsequent depolarization of excitable cells at resting... 

Radioiodinated derivatives have been prepared to define more closely the target site of a-conotoxins on the acetylcholine receptor (R. Myers, unpublished data). In membrane preparations from Torpedo electroplax, photoactivatable azidosalicylate derivatives of a-conotoxin GIA preferentially label the p and 7 subunits of the acetylcholine receptor. However, when the photoactivatable derivative is cross-linked to detergent solubilized acetylcholine receptor (AChR), only the 7 subunit is labeled. Since snake a-neurotoxins mainly bind to the a subunits of AChR and a-conotoxins compete directly with a-bungarotoxin, the cross-linking results above are both intriguing and problematic. 

Mamounas, L.A., and Molliver, M.E. Evidence for dual serotonergic projections to neocortex Axons from the dorsal and median raphe nuclei are differentially vulnerable to the neurotoxin p-chloroamphetamine (PCA). Exp Neurol 102 23-36, 1988. 

Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL. Diffusible, nonfibrillar ligands derived from Abetad 42) are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 1998 95 6448-6453. 

Axt, K.J., Commins, D.L., Vosmer, G., Seiden, L.S. alpha-Mcthyl-p-tyrosine pretreatment partially prevents methamphetamine-induced endogenous neurotoxin formation. Brain Res. 515 269, 1990. 

Ottoboni S, Caldera P, Trevor A, et al. Deuterium isotope effect measurements on the interactions of the neurotoxin l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine with monoamine oxidase B. J Biol Chem 1989 264(23) 13684-13688. 

G. Schiavo, F. Benfenati, B. Poulain, O. Rossetto, P. Polverino de Laureto, B. R. Das-Gupta, C. Montecucco, Tetanus and Botulinum-B Neurotoxins Block Neurotransmitter Release by Proteolytic Cleavage of Synaptobrevin , Nature 1992a, 359, 832-835 G. Schiavo, O. Rossetto, A. Santucci, B. R. DasGupta, C. Montecucco, Botulinum Neurotoxins are Zinc Proteins , J. Biol. Chem. 1992b, 267, 23479-23483. 

Chaddock, J.A., Purkiss, J.R., Friis, L.M., Broadbridge, J.D., Duggan, M.J. Fooks, S.J., Shone, C.C., Quinn, C.P. and Foster, K.A., Inhibition of vesicular secretion in both neuronal and nonneuronal cells by a retargeted endopeptidase derivate of Clostridium botulinum neurotoxin type A, Infect. Immun., 68, 2587-2593, 2000. 

Evans, D., Williams, R.S., Shone, C.C., Hambleton, P., Melling, J. and Dolly, J.O., Botulinum neurotoxin type B. Its purification, radioiodination and interaction with rat-brain synaptosomal membranes, Eur. I. Biochem., 154, 409-416, 1986. 

Hauser, D., Gibert, M., Boquet, P. and Popoff, M.R., Plasmid localization of a type E botulinal neurotoxin gene homologue in toxigenic Clostridium butyricum strains, and absence of this gene in non-toxigenic C. butyricum strains, FEMS Microbiol. Lett., 78, 251-255, 1992. 

Schiavo, G., Malizio, C., Trimble, W.S., Polverino de Laureto, P., Milan, G., Sugiyama, H., Johnson, E.A. and Montecucco, C., Botulinum G neurotoxin cleaves VAMP/synaptobrevin at a single Ala-Ala peptide bond, J. Biol. Chem., 269, 20213-20226, 1994. 

Williams, R.S., Tse, C.-K., Dolly, J.O., Hamblet, P. and Melling, J., Radioiodination of botulinum neurotoxin type A with retention of biological activity and its binding to brain synaptosomes, Eur. J. Bioch., 31, 437-445, 1983. 

Spencer, P., Nunn, P. B., Hugon, J., et al. (1987). Guam amyotrophic lateral sclerosis-parkinsonism-dementia linked to a plant excitant neurotoxin. Science237,517-522. 

Nonmetallic neurotoxins are frequently used in industry in manufacturing of chemicals and resins or as solvents. Some examples are hydrogen sulfide (which paralyzes specifically the nervous centers that control respiratory movement), carbon disulfide, -hexane, methyl -butyl ketone, and acrylamide. Exposure to all of these substances may occur through inhalation of vapors. In addition, carbondisufide and acrylamide may enter the system by dermal absorption. -Hexane and methyl -butyl ketone are not toxic by themselves but are activated by cytochrome P-450 to the neurotoxic hexanedione (CH3COCH2CH2COCH3). 

It has been known for many years that autonomic effector tissues (eg, gut, airways, bladder) contain nerve fibers that do not show the histochemical characteristics of either cholinergic or adrenergic fibers. Both motor and sensory NANC fibers are present. Although peptides are the most common transmitter substances found in these nerve endings, other substances, eg, nitric oxide synthase and purines, are also present in many nerve terminals (Table 6-1). Capsaicin, a neurotoxin derived from chili peppers, can cause the release of transmitter (especially substance P) from such neurons and, if given in high doses, destruction of the neuron. 

Escoubas, P, Diochot, S. and Corzo, G. (2000). Structure and pharmacology of spider venom neurotoxins. Biochimie 82 893-907. 

Neurotoxins produced by the body. Some normal body constituents are neurotoxic in excess. These incluse quinolinic acid (Fig. 25-11),889 3-hydroxykynurenine (Fig. 25-11 p. 1444),890 and homocysteine.891 Elevated levels of homocysteine are also associated with vascular disease and stroke (Chapter 24). 3-Hydroxykynurenine is a precursor to ommochrome pigments of insects and an intermediate in conversion of tryptophan into the nicotinamide ring of NAD in humans (Fig. 25-11). 6-Hydroxydopamine (Fig. 30-26), which may be formed in the body, is severely toxic to catecholaminergic neurons.892... 

Both the ease of use of this method for characterization of proteins and nucleic acids, and the ability to analyze many samples simultaneously for comparative purposes, have led to the prevalence of this technique. The drawbacks of a p oly acrylamide matrix is that acrylamide is a neurotoxin, the reagents must be combined extremely carefully, and the gels are not as pliable as most agarose gels. 

Cyanobacteria - the Jekyll and Hyde of marine organisms - are a novel source of potential new pharmaceutical compounds (2618-2620, 2662). On the other hand, toxic cyanobacterial blooms in lakes, rivers, and water storage reservoirs have occurred worldwide (2621, 2663, 2664). For example, 60 patients in a Brazil hemodialysis unit died after drinking water from a lake contaminated with cyanobacterial microcystins (2622), not unlike the toxicity of red tides (2623). Cyanobacteria also produce the highly toxic neurotoxin, p-N-methylamino-L-alanine, which may be produced by all cyanobacteria (2624, 2665). 

Another example of a quantal repeat—but with considerable variation in sequence—is seen in the keratin-associated proteins (KAPs). In sheep, these display pentapeptide and decapeptide consensus repeats of the form G—G—Q—P—S/T and C-C-Q/R—P—S/T—C/S/T—C—Q—P/T—S, respectively (Parry et al., 1979). Some of the positions, as indicated by the presence of a consensus sequence, contain residues that occur much more frequently than others, but the absolute conservation of a residue in any position is not observed. The decapeptide consists of a pair of five-residue repeats closely related, but different to that displayed by the pentapeptide. Although the repeats have an undetermined structure, the similarity of the repeat to a sequence in snake neurotoxin suggests that the pentapeptides will adopt a closed loop conformation stabilized by a disulphide bond between cysteine residues four apart (Fig. 5 Fraser et al., 1988 Parry et al, 1979). Relative freedom of rotation about the single bond connecting disulphide-bonded knots would give rise to the concept of a linear array of knots that can fold up to form a variety of tertiary structures. The KAPS display imperfect disulphide stabilization of knots and have interacting... 

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