Pharmacological properties of the potent epileptogenic amino acid dysiherbaine, a novel glutamate receptor agonist isolated from the marine sponge Dysidea herbacea

Dysiherbaine (DH) is a marine sponge-derived amino acid that causes seizure s upon injection into mice. In this report we investigate the behavioral ef fects and characterize the pharmacological activity of DH. DH induced convu lsive behaviors in mice with ED50 values of 13 pmol/mouse, i.c.v. and 0.97 mg/kg, i p. In rat brain synaptic membranes DH displaced binding of [H-3] k ainic acid (KA) and [H-3] alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropio nic acid (AMPA) with K-i values of 26 and 153 nM, respectively; in contrast , DH did not displace the N-methyl-D-aspartic acid (NMDA) receptor ligand [ H-3] CGS-19755. DH displaced [H-3]KA from recombinant GluR5 and GluR6 kaina te receptor subunits expressed in HEK293 cells with K-i values of 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 re ceptors with EC50 values of 9.7 mM and 210 nM, respectively. AMPA receptor currents were blocked by GYKI 53655, whereas KA receptor currents were bloc ked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Surprisingly, in calciu m imaging experiments we found that DH also activated recombinant mGluR5 re ceptors but did not activate mGluR1 receptors. DH did not activate glutamat e transporters or gamma -aminobutyric acid A (GABA(A))receptors. These resu lts indicate that DH is a potent non-NMDAtype agonist with very high affini ty for KA receptors, as well as a subtype-selective mGluR agonist. DH posse sses the most potent epileptogenic activity among the amino acids yet ident ified. This novel excitatory amino acid may prove useful for evaluating the physiological and pathological roles of non-NMDA receptors, especially KA receptors, in the central nervous system.