Muscarinic toxins from the venom of Dendroaspis snakes with agonist-like actions

Abstract

The venom of some Dendroaspis snakes contains small proteins (7500 mol. wt) that inhibit the binding of radiolabelled muscarinic antagonist to brain synaptomal membranes. There were no peptides described among muscarinic ligands until Adem et al. ( Biochim. biophys. Acta 968, 340–345, 1988) reported that muscarinic toxins (MTxs), MTx1 and 2 were able to inhibit 3H-QNB binding to rat brain membranes. Since MTxs inhibit around half of specific binding of 3H-quinuclidinyl benzilate ( 3H-QNB) and 3 H- N-methyl-scopolamine ( 3H-NMS), which do not discriminate between subtypes of muscarinic receptors, it has been proposed that MTxs might selectively bind to some subtype. MTx1 and 2 from Dendroaspis angusticeps almost completely inhibit the binding of 3H-pirenzepine ( 3H-PZ), a preferential M 1 muscarinic receptor subtype ligand to cerebral cortex synaptosomal membranes. A much higher concentration was needed to inhibit partially 3H-PZ binding to atrial muscarinic receptors. These results support the hypothesis that MTx1 and 2 may be m 1 selective muscarinic ligands. Similar activities have been found in Dendroaspis polylepis and D. viridis venoms, but with lower affinities. The K i obtained from inhibition curves of the binding of 3H-PZ showed that MTx1 has higher affinity for the putative M 1 muscarinic receptor subtype, followed by MTx2. DpMTx has lower affinity, while DvMTx seems to have the lowest affinity. All these peptides are devoid of anticholinesterase activity. Dendrotoxin and fasciculin from D. angusticeps venom do not inhibit the binding of muscarinic radioligands to cerebral cortex membranes. The injection of MTxs into dorsal hippocampus of rats immediately after training in an inhibitory avoidance task improves memory consolidation, as does oxotremorine. This improvement is antagonized by the joint administration of the muscarinic antagonist scopolamine. These results suggest that MTxs behave as a muscarinic agonist, at least in this case. Therefore, the muscarinic toxins from elapid snakes may be useful tools since they are proteins that might be selective muscarinic ligands, that seem to be agonists in the case of MTxs from D. angusticeps venom.