Waglerin-1 modulates gamma-aminobutyric acid activated current of murine hypothalamic neurons.

We examined the effect of Waglerin-1, a peptide of 22 amino acid residues purified from the venom of Wagler's pit viper (Trimeresurus wagleri), on the whole cell current response (I(GABA)) of freshly isolated murine hypothalamic neurons to gamma-aminobutyric acid (GABA). Although the application of 32 microM Waglerin-1 alone had no effect on membrane conductance, coapplication with GABA increased I(GABA) for 78 and suppressed I(GABA) for 44 of the 141 neurons examined. The potentiating effect of Waglerin-1 was associated with a leftward shift of the concentration-response relation of GABA without increasing peak I(GABA). This potentiating effect of Waglerin-1 on I(GABA) mimics diazepam. Furthermore, the benzodiazepine antagonist flumazenil antagonized Waglerin-1 potentiation of I(GABA), These observations suggest that Waglerin-1 acts on the benzodiazepine site of one type of GABA(A) receptor/channel complex to increase its affinity for agonist. In contrast, the depressant effect of Waglerin-1 was associated with a rightward shift of the concentration-response relation of GABA without depressing the maximal I(GABA); this suggests a competitive inhibition of a second class of GABAR. The ability of Waglerin-1 to suppress I(GABA) showed a positive correlation with a similar action of Zn++. As with Zn++, the depressant effect of Waglerin-1 on I(GABA) was more pronounced at negative holding potentials. These observations are discussed in terms of variation in the subunit composition of GABA receptors that murine central nervous system neurons express.