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GABAB receptor phosphorylation regulates KCTD12-induced K⁺ current desensitization
Lisa Adelfinger1, Rostislav Turecek2, Klara Ivankova1
1Department of Biomedicine, University of Basel, 4056 Basel, Switzerland.
Biochemical Pharmacology
|July 29, 2014
Summary
Two GABAB receptor desensitization pathways interact: serine-892 phosphorylation slows KCTD12-mediated desensitization, while KCTD12 assembly promotes phosphorylation, sharpening neuronal responses.
Area of Science:
- Neuroscience
- Molecular and Cellular Biology
- Pharmacology
Background:
- GABAB receptors, composed of GABAB1 and GABAB2 subunits, regulate neuronal activity by activating potassium channels.
- Receptor desensitization prevents excessive neuronal excitation, involving distinct mechanisms like protein kinase-A (PKA) activity and auxiliary KCTD subunits.
- KCTD12 binding to GABAB receptors accelerates desensitization by interfering with G-protein βγ subunit-mediated channel activation.
Purpose of the Study:
- To investigate the interplay between two GABAB receptor desensitization mechanisms: PKA-mediated serine-892 phosphorylation and KCTD12-induced desensitization.
- To determine if serine-892 phosphorylation influences KCTD12 function and vice versa.
- To elucidate the in vivo relevance of this cross-regulation in neuronal desensitization.
Main Methods:
- Utilized heterologous cell systems and primary hippocampal neuron cultures.
- Employed genetic manipulation, including KCTD12 knockout and serine-892 alanine knock-in mouse models.
- Measured GABAB receptor-activated potassium currents and assessed phosphorylation states.
Main Results:
- Serine-892 phosphorylation in GABAB2 rearranges KCTD12, significantly slowing KCTD12-induced desensitization.
- PKA activation decelerates fast desensitization in neurons, while PKA inhibition accelerates it.
- In vivo studies confirmed that serine-892 phosphorylation is essential for regulating KCTD12-mediated desensitization, and tonic phosphorylation normally limits KCTD12 effects.
Conclusions:
- GABAB receptor desensitization involves a cross-regulatory mechanism between serine-892 phosphorylation and KCTD12 activity.
- This interaction fine-tunes GABAB receptor signaling, with serine-892 phosphorylation acting as a brake on KCTD12-mediated desensitization.
- The interplay sharpens neuronal responses to repeated GABAB receptor activation, highlighting a novel regulatory circuit in synaptic transmission.
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