Inactivation of a quisqualate-sensitive glutamate receptor by photosensitive analogues of philanthotoxin

Three photosensitive, synthetic analogues of δ-philanthotoxin (PhTX-433) have been tested on the locust, excitatory nerve-muscle system. At 10 −9 M they inhibit reversibly the postjunctional currents (EPSCs) recorded from muscle fibres during motor nerve stimulation, mainly by non-competitively antagonizing postjunctional quisqualate-sensitive glutamate receptors (Quis-R), probably through open channel block. This use-dependent antagonism is characteristic of the philanthotoxins. When the preparation was irradiated with 270 nm U.V. during toxin application and nerve stimulation the EPSCs were inhibited irreversibly. Irradiation of the preparation alone or in the presence of philanthotoxins (e.g. PhTX-433) which are not photosensitive did not lead to irreversible inhibition of the EPSC. It is concluded that the three photosensitive toxins bind covalently to Quis-R in its open channel conformation during U.V. irradiation, thereby irreversibly blocking the channel gated by this receptor.