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Sci. STKE, 25 May 2004
[DOI: 10.1126/stke.2342004tr4]

Regulation of GABA Receptor Activity by Neurosteroids and Phosphorylation

Jeffrey Tasker

1Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA.

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*Corresponding author. E-mail: tasker@tulane.edu

Description

These two animations show two models for how neurosteroids and protein kinases regulate the flow of chloride ions (Cl) through ionotropic gamma-aminobutyric acid (GABA) receptors. The difference between the two models is the sequence of the phosphorylation and neurosteroid-binding events. In the first model, binding of the neurosteroid allopregnanolone (ALLO) occurs first and allows a protein kinase C (PKC) phosphorylation site to become accessible. Phosphorylation of the channel increases flux through the channel. In the second model, phosphorylation by PKC occurs first and allows the neurosteroid (ALLO) to bind and increase flux through the channel. In both animations, PKC activity is stimulated by heterotrimeric G proteins, which can be activated by G protein-coupled receptors (GPCRs). This provides a mechanism for cross talk between ion channels and GPCRs. The animations are animated gifs that have two parts: (i) a diagrammatic representation of the sequence of events at the channel in the membrane and (ii) a representative current trace of data obtained using electrophysiological techniques. These animations would be useful in teaching how allosteric modulators (neurosteroids) and covalent modulators (kinases) can work together as regulators of protein activity.

Animation 1. Neurosteroid Binding Exposes a Phosphorylation Site (Model A). This animation shows one model for how neurosteroids may increase Cl flux through a GABAA receptor. Binding of the neurosteroid (ALLO) allows a protein kinase C (PKC) phosphorylation site to become accessible. Phosphorylation of the channel increases flux through the channel, allowing more Cl ions to flow through the channel in the presence of GABA than when the channel is activated by GABA without prior phosphorylation. The top of this animated gif shows how the channel, the ligands, and G protein-activated PKC may be interacting at the plasma membrane. The bottom of the animation shows how these interactions affect the current trace recorded using electrophysiological techniques. In the current trace, the size of the signal is smaller in the absence of neurosteroid compared to the size of the signal after exposure to neurosteroid and subsequent phosphorylation of the channel.

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Animation 2. Phosphorylation Exposes a Neurosteroid Binding Site (Model B). This animation shows an alternative model for how neurosteroids and PKC may increase Cl flux through GABAA receptors. Binding of GABA to the phosphorylated channel produces ion flux. However, the phosphorylated channel is also able to interact with the neurosteroid (ALLO), which results in increased Cl flux in the presence of GABA. If PKC activity is inhibited, the channel is dephosphorylated by phosphatases (not shown), cannot bind the neurosteroid, and returns to a basal level of GABA-stimulated ion flux. The top of this animated gif shows how the channel, the ligands, and G protein-activated PKC may be interacting at the plasma membrane. The bottom of the animation shows how these interactions affect the current trace recorded using electrophysiological techniques. In the current trace, the size of the signal is smaller in the absence of neurosteroid compared to the size of the signal after phosphorylation and binding of neurosteroid.

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Educational Details

Learning Resource Type: Animation

Context: Undergraduate upper division, graduate, professional (degree program)

Intended Users: Teacher, learner

Intended Educational Use: Teach, learn

Discipline: Cell biology, molecular biology, neurobiology

Keywords: Signal transduction, channel, GABAergic, electrophysiology

Technical Details

Format: GIF

Size: 165 kb (animation 1), 195 kb (animation 2)

Related Resources

Perspective: J. Tasker, Coregulation of ion channels by neurosteroids and phosphorylation. Sci. STKE 2000, pe1 (2000). [Summary] [Full text]

Limits for Use

Cost: Free

Rights: This material may be downloaded, printed, linked to, and/or redistributed without modification for noncommercial, course-teaching purposes only, provided credit to STKE is included by listing the citation for the teaching resource.

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Citation: J. Tasker, Regulation of GABA receptor activity by neurosteroids and phosphorylation. Sci. STKE 2004, tr4 (2004).

© 2004 American Association for the Advancement of Science


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