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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
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Co-activation of GPCRs facilitate GIRK-dependent current
Alec F Condon1, Naeem Asad2, Timothy M Dore2
1The Vollum Institute, Oregon Health Sciences University, Portland, USA.
The Journal of Physiology
|September 19, 2022
Summary
Dopamine neuron activity is modulated by D2 and GABAB receptors acting on G protein-coupled inwardly rectifying potassium (GIRK) channels. This study reveals bidirectional interactions, where receptor co-activation facilitates GIRK currents, impacting dopamine neuron signaling.
Area of Science:
- Neuroscience
- Molecular Pharmacology
- Cellular Signaling
Background:
- Dopamine neuron activity relies on intrinsic properties and external inputs.
- Inhibitory D2 and GABAB receptors, both activating G protein-coupled inwardly rectifying potassium (GIRK) channels, are key modulators.
- Previous studies showed agonist co-application at saturating concentrations occludes GIRK current.
Purpose of the Study:
- To investigate the interaction between D2 and GABAB receptors using transient, sub-saturating agonist applications.
- To model the heterologous facilitation of GIRK currents based on G protein βγ subunit interactions.
- To understand how G protein βγ subunit levels influence GIRK current amplitude and kinetics.
Main Methods:
- Utilized brain slice electrophysiology to record GIRK channel currents.
- Applied transient, sub-saturating concentrations of D2 and GABAB receptor agonists.
- Developed computational models to simulate G protein βγ subunit interactions with GIRK channels.
Main Results:
- Co-application of D2 and GABAB agonists at sub-saturating levels induced bidirectional interactions, including facilitation and desensitization.
- Low tonic G protein βγ subunit levels facilitated GIRK current, while high levels caused occlusion.
- Transient receptor activation prolonged the kinetics of the induced GIRK current.
Conclusions:
- The cooperative interaction between G protein βγ subunits and GIRK channels dictates GPCR-dependent current amplitude and kinetics.
- Bidirectional interactions between D2 and GABAB receptor pathways significantly influence dopamine neuron signaling.
- Understanding individual GPCR system activity requires considering its context within other GPCR systems.
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