Neuroactive Steroids and Human Recombinant ρ1 GABA Receptors

@article{Li2007NeuroactiveSA,
  title={Neuroactive Steroids and Human Recombinant $\rho$1 GABA Receptors},
  author={Wenjun Li and Xiaochun Jin and Douglas F. Covey and Joe Henry Steinbach},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2007},
  volume={323},
  pages={236 - 247}
}
The γ-aminobutyric acid type C (GABAC) receptor is structurally related to the GABAA receptors, yet quite distinct physiologically and pharmacologically. Neuroactive steroids are known to be potent and efficacious modulators of the GABAA receptor, but they are less well characterized in their actions on the GABAC receptor. We have examined the actions of neuroactive steroids and analogs on ρ1 (GABAC) receptors expressed in Xenopus laevis oocytes, with two goals in mind. First, we tested a… 

Figures and Tables from this paper

Analysis of Modulation of the ρ1 GABAA Receptor by Combinations of Inhibitory and Potentiating Neurosteroids Reveals Shared and Distinct Binding Sites

Modulation of the human ρ1 GABAA receptor by several neurosteroids, individually and in combination, is analyzed in the framework of the coagonist concerted transition model to determine overlap of binding sites for several inhibitory and potentiating steroids.

Exploring the activity of an inhibitory neurosteroid at GABAA receptors

It is shown that the inhibitory neurosteroid pregnenolone sulphate directly modulates GABAA receptor kinetics by speeding up current decay at both neuronal and recombinant receptors.

Neurosteroids and GABA-A Receptor Function

Molecular mechanisms underlying neurosteroid action on the GABAA-receptor, mood changes, and cognitive functions are described.

Medicinal chemistry of ρ GABAC receptors.

The structure-activity relationship profiles of GABA analogs at the ionotropic ρ GABA(C) receptor are assessed to assess the development of selective phosphinic acid analogs of GABA and their potential use in sleep disorders, inhibiting theDevelopment of myopia, and in improving learning and memory.

Steroid Interaction with a Single Potentiating Site Is Sufficient to Modulate GABA-A Receptor Function

Overall, the data demonstrate that at a macroscopic level, the presence of a single wild-type steroid-binding site is sufficient to mediate responses to steroid, but both must be mutated to completely remove the effects of steroids.

Modulation of the human ρ1 GABAA receptor by inhibitory steroids

The data demonstrate that steroids and analogues differ with respect to conformational changes elicited by these drugs as well as sensitivity to the effects of mutations.

Neurochemicals for the Investigation of GABAC Receptors

A variety of neurochemicals that have been shown to be useful in distinguishing GABAC receptors from other receptors for the major inhibitory neurotransmitter GABA are described.

Medicinal chemistry of r GABA C receptors

The structure–activity relationship profiles of GABA analogs at the ionotropic r GABA C receptor are assessed and of particular interest is the development of selective phosphinic acid analogs of GABA and their potential use in sleep disorders, inhibiting theDevelopment of myopia, and in improving learning and memory.

References

SHOWING 1-10 OF 62 REFERENCES

Enantiomers of Neuroactive Steroids Support a Specific Interaction with the GABA-C Receptor as the Mechanism of Steroid Action

The results strongly suggest that the actions of these neuroactive steroids are mediated by interactions with chiral regions of the target protein, rather than by a change in membrane properties (including lateral pressure).

Differential modulation of the gamma-aminobutyric acid type C receptor by neuroactive steroids.

Structural comparison of these six neuroactive steroids reveals that the key parameter in determining the mode of modulation for the rho(1) receptor channel is the position of the hydrogen atom bound to the fifth carbon, imposing a trans- or cis-configuration in the backbone structure.

Pregnenolone sulfate block of GABAA receptors: mechanism and involvement of a residue in the M2 region of the α subunit

Pregnenolone sulfate is a sulfated neurosteroid which reduces the responses of the γ‐aminobutyric acid A (GABAA) receptor and its actions on single‐channel currents from recombinant GABAA receptors formed from α1, β2 and γ2L subunits are analysed.

A single amino acid confers barbiturate sensitivity upon the GABA ρ1 receptor

It is demonstrated that both δ‐hexachlorocyclohexane (δ‐HCH; 1–100 μM), a positive allosteric modulator of the GABAA receptor, and the anaesthetic pentobarbitone have no effect on GABA‐evoked currents mediated by wild‐type ρ1 recombinant receptors.

Neuroactive steroids and inhibitory neurotransmission: Mechanisms of action and physiological relevance

Selective antagonism of 5alpha-reduced neurosteroid effects at GABA(A) receptors.

A steroid analog, (3alpha,5alpha)-17-phenylandrost-16-en-3-ol (17PA), that selectively antagonized neurosteroid potentiation of GABA responses and antagonized 5alpha-reduced steroid potentiation and gating in hippocampal neurons and inhibited anesthetic actions in X. laevis tadpoles.

Selective Antagonism of 5-Reduced Neurosteroid Effects at GABAA Receptors

A steroid analog, (3 ,5 )-17-phenylandrost-16-en-3-ol (17PA), is reported that selectively antagonized neurosteroid potentiation of GABA responses and antagonized both the response augmentation and the direct gating of GABA receptors by 5 -reduced potentiating steroids.

3β-Hydroxypregnane Steroids Are Pregnenolone Sulfate-Like GABAA Receptor Antagonists

3β-hydroxypregnane steroids are not direct antagonists of potentiating steroids but rather are noncompetitive, likely state-dependent, blockers of GABAAreceptors Nevertheless, these steroids may be useful functional blockers of potentiation steroids when used at concentrations that do not affect baseline neurotransmission.

Insight into the mechanism of action of neuroactive steroids.

A universal model is presented wherein anesthetic compounds like NSs can potentiate or inhibit the activity of ligand-gated ion channels distinct from interaction with alternative binding sites.

A single amino acid confers barbiturate sensitivity upon the GABA rho 1 receptor.

It is demonstrated that both delta-hexachlorocyclohexane (delta-HCH; 1-100 microM), a positive allosteric modulator of the GABAA receptor, and the anaesthetic pentobarbitone have no effect on GABA-evoked currents mediated by wild-type rho 1 recombinant receptors.
...