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Cyclic AMP-dependent protein kinase phosphorylation facilitates GABA(B) receptor-effector coupling
A Couve1, P Thomas, A R Calver
1Medical Research Council Laboratory of Molecular Cell Biology and Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
Nature Neuroscience
|April 27, 2002
Summary
Phosphorylation of GABA(B) receptors by PKA at Ser892 enhances their membrane stability, alleviating desensitization of synaptic inhibition. This finding challenges the view of phosphorylation as a universal negative modulator.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Signaling
Background:
- GABA (gamma-aminobutyric acid)(B) receptors are crucial for slow synaptic inhibition in the central nervous system.
- These receptors are heterodimeric G protein-coupled receptors (GPCRs).
- Their functional coupling to ion channels can undergo desensitization.
Purpose of the Study:
- To investigate the mechanisms regulating GABA(B) receptor function and desensitization.
- To identify specific molecular players involved in modulating GABA(B) receptor activity.
- To challenge established paradigms regarding GPCR phosphorylation.
Main Methods:
- Investigated the functional coupling of GABA(B)R1/GABA(B)R2 receptors to inwardly rectifying K(+) channels.
- Utilized biochemical and cellular assays to study receptor phosphorylation.
- Examined the role of cyclic AMP (cAMP)-dependent protein kinase (PKA) and its target residue Ser892.
- Assessed the impact of forskolin and beta-adrenergic receptor activation on phosphorylation.
- Measured changes in receptor membrane stability.
Main Results:
- Functional coupling of GABA(B) receptors to K(+) channels desensitizes rapidly.
- Phosphorylation of Ser892 in the GABA(B)R2 tail by PKA alleviates this desensitization.
- Basal phosphorylation of Ser892 occurs in rat brain and cultured neurons.
- cAMP-elevating pathways (forskolin, beta-adrenergic receptors) positively modulate Ser892 phosphorylation.
- GABA(B) receptor agonists decrease receptor phosphorylation.
- Phosphorylation of Ser892 enhances GABA(B) receptor membrane stability.
Conclusions:
- Signaling pathways activating PKA significantly impact GABA(B) receptor-mediated synaptic inhibition.
- Phosphorylation of Ser892 by PKA is a key mechanism for regulating GABA(B) receptor function.
- This study demonstrates that phosphorylation can be a positive modulator of GPCR activity, contrary to common assumptions.
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