To Gate or not to Gate: Are the Delta Subunits in the Glutamate Receptor Family Functional Ion Channels?

The two delta receptor subunits remain the most puzzling enigma within the ionotropic glutamate receptor family. Despite the recent elucidation of the ligand-binding domain structure of delta2, many fundamental questions with regard to the subunits’ mechanism of function still remain unanswered. Of necessity, the majority of studies on delta receptors focused on the metabotropic function of delta2, since electrophysiological approaches to date are limited to the characterization of spontaneous currents through the delta2-lurcher mutant. Indeed, accumulated evidence primarily from delta2-deficient transgenic mice suggest that major physiological roles of delta2 are mediated via metabotropic signaling by the subunit’s C terminus. Why then would the subunits retain a conserved ion channel domain if they do not form functional ion channels? Any progress with regard to ionotropic function of the two delta subunits has been hampered by their largely unknown pharmacology. Even now that a pharmacological profile for delta2 is being established on the basis of the ligand-binding domain structure, wild-type delta2 channels in heterologous expression systems stay closed in the presence of molecules that have been demonstrated to bind to the receptor’s ligand-binding domain. In this paper, we review the current knowledge of delta subunits focusing on the disputed ionotropic function.