Crotoxin is a potent neurotoxin from the venom of Crotalus durissus terrificus. It is composed of two subunits: a basic phospholipase A2 with low toxicity (component B) and an acidic protein seemingly devoid of intrinsic biological activity (component A). Crotoxin and its isolated phospholipase subunit block the depolarisation caused by cholinergic agonists on the isolated electroplaque from Electrophorus electricus. The other component, which is inactive when applied alone, enhances the pharmacological activity of the phospholipase when the two components are used together. Crotoxin also blocks the increase of z2Na+ efflux caused by carbamylcholine from excitable microsacs prepared from Torpedo marmorata electric organ. Crotoxin therefore acts postsynaptically, but does not interfere with the binding of a-toxin from Nu@ nigricollis to the nicotinic cholinergic receptor site. Instead, like local anesthetics, it stabilizes a desensitized form of the acetylcholine receptor characterized by its high affinity for agonists. The phospholipase component B binds in a nonsaturable manner to receptor-rich membranes. In contrast, component A does not bind to acetylcholine receptor-rich membranes, but completely prevents the non-saturable binding of component B. When the two components are applied together, a saturable binding of the latter is observed with the acetylcholine receptor-rich membranes.Crotoxin, the major component of the brazilian rattle-snake (Crotalus durissus terrificus) venom is a very potent neurotoxin which possesses a phospholipase activity [l]. It is a complex of two distinct protein subunits [2,3] : a strongly basic component (component B, M , 12000) which carries the phospholipase activity and an acidic protein (component A, M , 10000) which has no enzymatic activity and is not toxic by itself. Whereas the isolated subunits are either not or only a little toxic, they recombine into a complex which exhibits the same toxicity as the original material [4,5].The lethal effect of crotoxin has generally been attributed to a presynaptic blockage of the neuromuscular transmission [6]. At this level, it causes a reduction of acetylcholine release by the nerve terminals similar to that observed with /l-bungarotoxin [7], notexin [8,9] and taipoxin [lo]. However, having observed a depression of the response to acetylcholine of the isolated denervated rat diaphragm, VitalBrazil [ l l ] concluded that crotoxin also acts at the postsynaptic level in the mammals. In order to examine a possible postsynaptic action of crotoxin without interference with its presynaptic action, we studied the effect of crotoxin on two postsynapticEnzyme. Phospholipase A2 (EC 3.1.1.4) preparations : the isolated electroplaque from Electrophorus electricus and the acetylcholine receptor-rich membranes from Torpedo marmorata. Crotoxin affects the response of both preparations to cholinergic agonists, and our observations suggest how interactions between the two subunits increase the pharmacological effect of the phospholipase component...
Several snake venom neurotoxins are larger and more complex than the well-studied group of postsynaptic toxins exemplified by a-bungarotoxin. Several of these, exemplified by ,-bungarotoxin, show phospholipase A2 activity (phosphatide 2-acylhydrolase, EC 3.1.1.4) when tested in the presence of detergents. The high hemolytic activity of crotoxin, the neurotoxin of Crotalus durissus terrificus, in the presence of lecithin has been attributed to this activity. The phospholipase A2 activity of several snake venom proteins has now been compared under the physiological conditions of the hemolysis tests.It appears that only the basic component of crotoxin, B, is enzymatically active, and that its activity is not inhibited by component A under these conditions, or in the presence of deoxycholate. Phosphatidylserine is found to be digested more readily than egg white phosphatidylcholine; and also causes hemolysis in conjunction with much lower levels of crotoxin. In neither case is calcium required or stimulating.Phospholipase from Crotalus adamanteus, which is not neurotoxic, digests phosphatidylcholine more rapidly than does crotoxin, but phosphatidylserine more slowly; yet it is slightly less active than crotoxin in the hemolysis test with phosphatidylcholine, and much less with phosphatidylserine. The digestion of several phospholipids by either enzyme fails to release the expected protons in the absence of detergents at 37°. P-Bungarotoxin, highly neurotoxic, has negligible phospholipase A2 activity in the absence of detergents, and is almost nonhemolytic in conjunction with all phospholipids tested.Binding studies with 125I4abeled compounds show that rabbit erythrocytes and ghosts have much greater affinity for crotoxin than for jP-bungarotoxin and do not bind Crotalus adamanteus phospholipase. The crotoxin complex is split in the course of inding, with only component B, the hemolytic component, becoming bound. It appears that the role of component A may be to diminish the nonspecific binding tendency of component B.Our data appear to be consistent with the concepts that affinity to membranes, particularly to specific sites on synaptic membranes, is the critical requirement for (3 type neurotoxicity, and that this property, at least in some instances, has evolved from phospholipase A2 enzymes, but does not necessarily require retention and expression of enzymatic activity.When the neurotoxin of the Brazilian rattlesnake (Crotalus durissus terrificus) was isolated in pure crystalline form in 1938 and was found to also carry the indirect (i.e., lecithin-dependent) hemolytic activity of that venom (1), it was then suggested (and has since been reiterated) that the ability of crotoxin to attack phospholipids might represent the basis of its neurotoxic potency.When, many years later, after crotoxin had been shown to consist of two proteins (2), the surprising finding was made that high neurotoxicity required the presence of both components (3-5), while in regard to hemolytic activity the larger and basic compone...
We determine temperature effect on the absorption and reduced scattering coefficients (mu(a) and mu(s)(')) of human forearm skin. Optical and thermal simulation data suggest that mu( a) and mu(s)(') are determined within a temperature-controlled depth of approximately 2 mm. Cutaneous mu(s)(') change linearly with temperature. Change in mu(a) was complex and irreversible above body normal temperatures. Light penetration depth (delta) in skin increased on cooling, with considerable person-to-person variations. We attribute the effect of temperature on mu(s)(') to change in refractive index mismatch, and its effect on mu(a) to perfusion changes. The reversible temperature effect on mu (s)(' ) was maintained during more than 90 min. contact between skin and the measuring probe, where temperature was modulated between 38 and 22 degrees C for multiple cycles While temperature modulated mu(s)(' ) instantaneously and reversibly, mu(a) exhibited slower response time and consistent drift. There was a statistically significant upward drift in mu(a) and a mostly downward drift in mu( s)(') over the contact period. The drift in temperature-induced fractional change in mu(s)(') was less statistically significant than the drift in mu(s)('). Deltamu( s)(') values determined under temperature modulation conditions may have less nonspecific drift than mu(s)(') which may have significance for noninvasive determination of analytes in human tissue.
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