Psychopharmacology

, Volume 231, Issue 17, pp 3493–3501

Phosphatidylinositol 4,5-bisphosphate depletion fails to affect neurosteroid modulation of GABAA receptor function

  • Steven Mennerick
  • Amanda A. Taylor
  • Charles F. Zorumski
Original Investigation
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Abstract

Rationale

Neurosteroids and likely other lipid modulators access transmembrane sites on the GABAA receptor (GABAAR) by partitioning into and diffusing through the plasma membrane. Therefore, specific components of the plasma membrane may affect the potency or efficacy of neurosteroid-like modulators. Here, we tested a possible role for phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that governs activity of many channels and transporters, in modulation or function of GABAARs.

Objectives

In these studies, we sought to deplete plasma-membrane PIP2 and probe for a change in the strength of potentiation by submaximal concentrations of the neurosteroid allopregnanolone (3α5αP) and other anesthetics, including propofol, pentobarbital, and ethanol. We also tested for a change in the behavior of negative allosteric modulators pregnenolone sulfate and dipicrylamine.

Methods

We used Xenopus oocytes expressing the ascidian voltage-sensitive phosphatase (Ci-VSP) to deplete PIP2. Voltage pulses to positive membrane potentials were used to deplete PIP2 in Ci-VSP-expressing cells. GABAARs composed of α1β2γ2L and α4β2δ subunits were challenged with GABA and 3α5αP or other modulators before and after PIP2 depletion. KV7.1 channels and NMDA receptors (NMDARs) were used as positive controls to verify PIP2 depletion.

Results

We found no evidence that PIP2 depletion affected modulation of GABAARs by positive or negative allosteric modulators. By contrast, Ci-VSP-induced PIP2 depletion depressed KV7.1 activation and NMDAR activity.

Conclusions

We conclude that despite a role for PIP2 in modulation of a wide variety of ion channels, PIP2 does not affect modulation of GABAARs by neurosteroids or related compounds.

Keywords

Anesthetic Anticonvulsant Neurosteroid GABA Inhibition Membrane Phosphatidylinositol 4,5-bisphosphate 

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Steven Mennerick
    • 1
    • 2
    • 3
  • Amanda A. Taylor
    • 1
  • Charles F. Zorumski
    • 1
    • 2
    • 3
  1. 1.Department of PsychiatryWashington University School of MedicineSt. LouisUSA
  2. 2.Department of Anatomy and NeurobiologyWashington University School of MedicineSt. LouisUSA
  3. 3.Taylor Family Institute for Innovative Psychiatric ResearchWashington University School of MedicineSt. LouisUSA

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