Neurosteroid modulation of recombinant ionotropic glutamate receptors

Brain Res. 1998 Aug 24;803(1-2):153-60. doi: 10.1016/s0006-8993(98)00644-1.

Abstract

Pregnenolone sulfate (PS) is an abundant neurosteroid that can potentiate or inhibit ligand gated ion channel activity and thereby alter neuronal excitability. Whereas PS is known to inhibit kainate and AMPA responses while potentiating NMDA responses, the dependence of modulation on receptor subunit composition remains to be determined. Toward this end, the effect of PS on recombinant kainate (GluR6), AMPA (GluR1 or GluR3), and NMDA (NR1(100)+NR2A) receptors was characterized electrophysiologically with respect to efficacy and potency of modulation. With Xenopus oocytes expressing GluR1, GluR3 or GluR6 receptors, PS reduces the efficacy of kainate without affecting its potency, indicative of a noncompetitive mechanism of action. Conversely, with oocytes expressing NR1(100)+NR2A subunits, PS enhances the efficacy of NMDA without affecting its potency. Whereas the modulatory efficacy, but not the potency, of PS is increased two-fold by co-injection of NR1(100)+NR2A cRNAs as compared with NR1(100) cRNA alone, there is little or no effect of the NR2A subunit on efficacy or potency of pregnanolone (or epipregnanolone) sulfate as an inhibitor of the NMDA response. This suggests that the NR2A subunit controls the efficacy of neurosteroid enhancement, but not inhibition, which is consistent with our previous finding that potentiating and inhibitory steroids act at distinct sites on the NMDA receptor. This represents a first step towards understanding the role of subunit composition in determining neurosteroid modulation of ionotropic glutamate receptor function.

MeSH terms

  • Adrenal Cortex Hormones
  • Animals
  • Dose-Response Relationship, Drug
  • Kainic Acid / antagonists & inhibitors
  • Kainic Acid / pharmacology
  • Microinjections
  • Neurotransmitter Agents / pharmacology*
  • Neurotransmitter Agents / physiology
  • Oocytes / cytology
  • Oocytes / drug effects
  • Pregnenolone / pharmacology
  • RNA, Complementary / administration & dosage
  • RNA, Complementary / drug effects
  • RNA, Complementary / pharmacology
  • Rats
  • Receptors, AMPA / drug effects
  • Receptors, AMPA / genetics
  • Receptors, AMPA / metabolism*
  • Receptors, Kainic Acid / drug effects
  • Receptors, Kainic Acid / genetics
  • Receptors, Kainic Acid / metabolism*
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Recombinant Proteins / drug effects
  • Recombinant Proteins / metabolism*
  • Xenopus

Substances

  • Adrenal Cortex Hormones
  • Gluk2 kainate receptor
  • Neurotransmitter Agents
  • RNA, Complementary
  • Receptors, AMPA
  • Receptors, Kainic Acid
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Proteins
  • glutamate receptor ionotropic, AMPA 3
  • pregnenolone sulfate
  • Pregnenolone
  • Kainic Acid
  • glutamate receptor ionotropic, AMPA 1