CHANNELS, RECEPTORS, AND ELECTRICAL SIGNALING |
Effects on membrane capacitance of steroids with antagonist properties at GABAA receptors
Steven Mennerick 1*, Michael Lamberta 2, Hong-Jin Shu 2, Joshua Hogins 3, Cunde Wang 2, Douglas F Covey 2, Lawrence N Eisenman 2 and Charles F Zorumski 2
1 Washington University in St. Louis
2 Washington Univ
3 Washington University
* To whom correspondence should be addressed. E-mail: menneris{at}psychiatry.wustl.edu.
Submitted on November 8, 2007
Revised on December 20, 2007
Accepted on 29 February 2008
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Abstract |
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We investigated the electrophysiological signature of neuroactive steroid interactions with the plasma membrane. We found that charged, sulfated neuroactive steroids, those that exhibit non-competitive antagonism of GABAA receptors, altered capacitive charge movement in response to voltage pulses in cells lacking GABA receptors. Uncharged steroids, some of which are potent enhancers of GABAA receptor activity, produced no alteration in membrane capacitance. We hypothesized that the charge movements might result from physical translocation of the charged steroid through the transmembrane voltage, as has been observed previously with several hydrophobic anions. However, the charge movements and relaxation time constants of capacitive currents did not exhibit the Boltzmann-type voltage dependence predicted by a single barrier model. Further, a fluorescently tagged analogue of a sulfated neurosteroid altered membrane capacitance similar to the parent compound but produced no voltage-dependent fluorescence change, a result inconsistent with a strong change in the polar environment of the fluorophore during depolarization. These findings suggest that negatively charged sulfated steroids alter the plasma membrane capacitance without physical movement of the molecule through the electric field.
Key Words:
capacitance, convulsant, epilepsy, membrane, neurosteroid, pregnenolone sulfate
