Abstract
Dysiherbaine (DH) is a novel marine sponge-derived amino acid and is highly epileptogenic in mice. Administration of DH induced long lasting convulsive behaviors with ED50 values of 13 pmol/mouse, i.c.v., and 0.97 mg/kg, i.p. which is 5-7 time more potent than that of domoic acid. In rat brain synaptic membranes DH displaced binding of [3H]kainic acid (KA) and [3H]AMPA with Ki values of 26 and 153 nM, respectively. In contrast, DH did not displace the NMDA receptor ligand [3H] CGS-19755. DH also displaced [3H]KA from the recombinant GluR5 and GluR6 at Ki value of each 0.74 and 1.2 nM, respectively. In whole-cell voltage clamp recordings from cultured rat hippocampal neurons DH evoked inward currents from both AMPA and KA receptors with EC50 values of 9.7 μM and 210 nM, respectively. Additionally DH activated mGlu5 but not mGluR1. In the heteromerically expressed KA receptors, GluR5-KA2, in HEK 293 cells DH evoked desensitizing inward current. However, the inward current arose again after removal of DH. Application of glutamate to this "activated" receptor can further elicit the desensitizing inward current. Surprisingly, non-desensitizing inward current was gated by CNQX, a classically defined antagonist. These results demonstrated that DH can activate only high affinity GluR5 site in the heteromerically assembled GluR5/KA2, and that for the first time the low affinity subunit, KA2, can gate channel currents individually upon application of the agonists in quite unexpected ways. [Jpn J Physiol 54 Suppl:S13 (2004)]
