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 mu M 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.