Novel Three-Finger Neurotoxins from Cobra Venom Interact with GABA and Nicotinic Acetylcholine Receptors.

Cobra venoms contain three-finger toxins (TFT) including α-neurotoxins efficiently binding nicotinic acetylcholine receptors (nAChRs). As shown recently, several TFTs block GABA receptors (GABARs) with different efficacy, an important role of the TFTs central loop in binding to these receptors being demonstrated. We supposed that the positive charge (Arg36) in this loop of α-cobratoxin may explain its high affinity to GABAR and here studied α-neurotoxins from African cobra venom for their ability to interact with GABAARs and nAChRs. Three α-neurotoxins, close homologues of the known long neurotoxins 1 and 2, were isolated and sequenced. Their analysis on and α7 nAChRs, as well as on acetylcholine binding proteins and on several subtypes of GABARs, showed that all toxins interacted with the GABAR much weaker than with the nAChR: one neurotoxin was almost as active as α-cobratoxin, while others manifested lower activity. The earlier hypothesis about the essential role of Arg36 as the determinant of high affinity to GABAR was not confirmed, but the results obtained suggest that the toxin loop III may contribute to the efficient interaction of some long-chain neurotoxins with GABAR. One of isolated toxins manifested different affinity to two binding sites on nAChR.