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

摘要

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 pharma-cological activity of OH. OH 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 OH displaced binding of [3H]kainic acid (KA) and [3H]a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) with K1 values of 26 and 153 nM, respectively; in contrast, OH did not displace the N-methyl-o-aspartic acid (NMOA) receptor ligand [3H]CGS-1 9755. OH displaced [3H]KA from recombinant GIuR5 and GIuR6 kainate receptor subunits expressed in HEK293 cells with K~ values of 0.74 and 1.2 nM, respectively. In whole-cell voltage-clamp recordings from cultured rat hippocampal neurons, OH evoked inward currents from both AMPA and KA receptors with EC50values of 9.7 ~tM 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-di-one (CNQX). Surprisingly, in calcium imaging experiments we found that OH also activated recombinant mGluR5 receptors but did not activate mGluRl receptors. OH did not activate glutamate transporters or y-aminobutyric acid A (GABAA) re-ceptors. These results indicate that OH is a potent non-NMOA-type agonist with very high affinity for KA receptors, as well as a subtype-selective mGluR agonist. OH possesses the most potent epileptogenic activity among the amino acids yet iden-tified. 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 ner-vous system.