Abstract
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]α-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 theN-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 γ-aminobutyric acid A (GABAA) 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.
Footnotes
- Received July 7, 2000.
- Accepted October 16, 2000.
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Send reprint requests to: Dr. Ryuichi Sakai, School of Fisheries Sciences, Kitasato University, Kesen-gun Sanriku-cho, Iwate, 022-0101 Japan. E-mail: r.sakai{at}kitasato-u.ac.jp
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This work was partly supported by the Ministry of Education, Science and Culture, Japan (Grant 09760196) and generous grants from Naito Foundation to R.S. G.T.S. was supported by a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression. A.C. was supported by a grant from Auen Foundation.
- The American Society for Pharmacology and Experimental Therapeutics
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