Received for publication March 29, 2005.
Revised May 10, 2005.
Accepted for publication May 19, 2005.

Divergent pharmacological activity of novel marine-derived excitatory amino acids on glutamate receptors

Abstract

Kainate receptors show a particular affinity for a variety of natural source compounds, including dysiherbaine (DH), a potent agonist derived from the marine sponge Dysidea herbacea. In this study, we characterized the pharmacological activity and structural basis for subunit selectivity of neodysiherbaine (neoDH) and MSVIII-19, which are natural and synthetic analogues of DH, respectively. NeoDH and MSVIII-19 differ from DH in the composition of two functional groups that confer specificity and selectivity for ionotropic glutamate receptors. In radioligand binding assays, neoDH displayed a 15-25-fold lower affinity relative to that of DH for GluR5 and GluR6 kainate receptor subunits but a 7-fold higher affinity for KA2 subunits, whereas MSVIII-19 displaced [³H]kainate only from GluR5 subunits but not GluR6 or KA2 subunits. NeoDH was an agonist for kainate and AMPA receptors in patch-clamp recordings; in contrast, MSVIII-19 acted as a potent antagonist for homomeric GluR5 receptors currents with weaker activity on other kainate and AMPA receptors. Neither neoDH nor MSVIII-19 activated group I metabotropic GluRs. Homology modeling suggests that two critical amino acids confer the high degree of selectivity between the dysiherbaine analogues and the GluR5 and KA2 subunits. In summary, these data describe the pharmacological activity of two new compounds, one of which is a selective GluR5 receptor antagonist that will be of use for understanding native receptor function and designing more selective ligands for kainate receptors.

Key words: agonist, excitatory synaptic transmission, glutamate receptor, homology modeling, kainate receptor, structure-function

This article has been cited by other articles:

				L. L. Lash, J. M. Sanders, N. Akiyama, M. Shoji, P. Postila, O. T. Pentikainen, M. Sasaki, R. Sakai, and G. T. Swanson Novel Analogs and Stereoisomers of the Marine Toxin Neodysiherbaine with Specificity for Kainate Receptors J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 484 - 496. [Abstract] [Full Text] [PDF]

				J. M. Sanders, O. T. Pentikainen, L. Settimo, U. Pentikainen, M. Shoji, M. Sasaki, R. Sakai, M. S. Johnson, and G. T. Swanson Determination of Binding Site Residues Responsible for the Subunit Selectivity of Novel Marine-Derived Compounds on Kainate Receptors Mol. Pharmacol., June 1, 2006; 69(6): 1849 - 1860. [Abstract] [Full Text] [PDF]