Vol. 296, Issue 2, 650-658, February 2001

Pharmacological Properties of the Potent Epileptogenic Amino Acid Dysiherbaine, a Novel Glutamate Receptor Agonist Isolated from the Marine Sponge Dysidea herbacea

Ryuichi Sakai, Geoffrey T. Swanson, Keiko Shimamoto, Tim Green, Anis Contractor, Andrea Ghetti, Yoshiko Tamura-Horikawa, Chie Oiwa and Hisao Kamiya

School of Fisheries Sciences, Kitasato University, Kesen-gun Sanriku-cho, Iwate, Japan (R.S., C.O., H.K.); Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California (G.T.S., T.G., A.C., A.G.); and the Suntory Institutes for Bioorganic Research (K.S.) and for Biomedical Research (Y.T-H.), Mishima-gun, Osaka, Japan

Dysiherbaine (DH) is a marine sponge-derived amino acid that causes seizures upon injection into mice. In this report we investigate the behavioral effects and characterize the pharmacological activity of DH. DH induced convulsive 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 [³H]kainic acid (KA) and [³H]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic 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 [³H]CGS-19755. DH displaced [³H]KA from recombinant GluR5 and GluR6 kainate 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 receptors with EC₅₀ values of 9.7 µM and 210 nM, respectively. AMPA receptor currents were blocked by GYKI 53655, whereas KA receptor currents were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Surprisingly, in calcium imaging experiments we found that DH also activated recombinant mGluR5 receptors but did not activate mGluR1 receptors. DH did not activate glutamate transporters or -aminobutyric acid A (GABA_A) receptors. These results indicate that DH is a potent non-NMDA-type agonist with very high affinity for KA receptors, as well as a subtype-selective mGluR agonist. DH possesses the most potent epileptogenic activity among the amino acids yet identified. 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.