Pharmacology of delta2 glutamate receptors: effects of pentamidine and protons.
The properties of delta2 receptors, which have homology to glutamate receptors but are not gated by glutamate, were studied using the constitutively active Lurcher mutant delta2(A654T) expressed in Xenopus oocytes. The macroscopic current through delta2(A654T) channels in voltage-clamped oocytes was defined as the difference between the holding current measured in the presence of extracellular Na(+) and that in the presence of the large impermeant cation N-methyl-d-glucamine. A-to-T mutations in the delta1 subunit and in NMDA (N-methyl-d-aspartate) receptor subunits, at positions equivalent to delta2(A654T), did not produce constitutively active channels. The current through delta2(A654T) channels was reduced by pentamidine and 9-tetrahydroaminoacridine, antagonists that also inhibit NR1/NR2B NMDA receptors but not AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. Block of delta2(A654T) currents by these two antagonists was incomplete and weakly voltage-dependent, in contrast to the block of NR1/NR2B receptors, which was complete and strongly voltage-dependent. Pentamidine inhibited a constitutively active NR1(T648A)/NR2B NMDA receptor in a manner similar to its inhibition of a glutamate-gated wild-type NMDA receptor, but different from its inhibition of constitutively active delta2(A654T) receptors. Currents gated by delta2(A654T) were sensitive to the extracellular pH, being smaller at acidic than at alkaline pH, with a pH IC(50) value of 7.47 and a maximum inhibition of 70%. It is concluded that delta2(A654T) channels have some properties in common with NMDA channels but also have characteristics that are different from these receptors. Compounds such as pentamidine may be useful for studies of native delta2 receptors.
Williams
Keith
K
Department of Physiology and Pharmacology, State University of New York Health Science Center, Brooklyn, 450 Clarkson Avenue, Box 31, Brooklyn, NY 11203-2098, USA. Keith.Williams@Downstate.edu
Dattilo
Michael
M
Sabado
Thomas N
TN
Kashiwagi
Keiko
K
Igarashi
Kazuei
K
D000465:Algorithms; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003001:Cloning, Molecular; D005260:Female; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008818:Mice, Neurologic Mutants; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000502:physiology; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010419:Pentamidine / Q000494:pharmacology*; D011522:Protons; D018091:Receptors, AMPA / Q000187:drug effects; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000235:genetics; D013619:Tacrine / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D011522:Protons; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C107913:glutamate receptor delta 2; D013619:Tacrine; D010419:Pentamidine