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Characterization of a novel family of GABAb receptor interacting proteins - KCTD8, 12, 12b, and 16

Metz, Michaela. Characterization of a novel family of GABAb receptor interacting proteins - KCTD8, 12, 12b, and 16. 2009, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_8934

Abstract

GABAB receptors are the G-protein coupled receptors for -aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. They are heteromeric GPCRs which function as heterodimers composed of the GABAB1 and GABAB2 subunit. Presynaptic and postsynaptic GABAB receptors regulate Ca- and K-channels respectively via the G subunits. Furthermore, GABAB receptors can activate and inhibit adenylyl cyclase through the Gi/o and G subunits. Proteins that interact with GABAB receptors at the plasma membrane most likely contribute to the functional heterogeneity observed with native GABAB responses.
We identified members of the K+ tetramerization domain containing (KCTD) protein family as novel GABAB receptor interacting proteins using immuno-affinity purification experiments from native mouse brain tissue. In separate affinity purification experiments, these proteins were also found to be associated with native Ca-channels. We have shown that native GABAB receptor exist as heteromultimers in a high molecular weight protein complex, tightly associated with KCTD8, 12, 12b, and 16.
KCTDs are able to form homo- and heterodimers, thus re-enforcing their role in complex formation with the GABAB receptor. We show that the KCTD-binding site is located within the intracellular C-term of the GABAB2 subunit and that KCTDs interact with the receptor via their conserved N-termini. In addition, coassembly with KCTDs leads to alterations of GABAB receptor properties, such as an increase in agonist potency and alterations in G-protein signaling. When compared, the spatial distribution and the functional properties of KCTD8, 12, 12b, and 16 suggest overlapping but also distinct properties in the context of GABAB receptor function. In summary, this dissertation reveals KCTD8, 12, 12b, and 16 as important players within the GABAB receptor signaling complex and designates them as novel auxiliary subunits of the GABAB receptor.
Advisors:Bettler, Bernhard
Committee Members:Barde, Yves-Alain
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Physiology > Molecular Neurobiology Synaptic Plasticity (Bettler)
Item Type:Thesis
Thesis no:8934
Bibsysno:Link to catalogue
Number of Pages:128
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:41
Deposited On:19 Feb 2010 13:41

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