Pharmacological characterization of GABAB receptor subtypes assembled with auxiliary KCTD subunits

Rajalu, M. and Fritzius, T. and Adelfinger, L. and Jacquier, V. and Besseyrias, V. and Gassmann, M. and Bettler, B.. (2015) Pharmacological characterization of GABAB receptor subtypes assembled with auxiliary KCTD subunits. Neuropharmacology, 88. pp. 145-154.

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Official URL: https://edoc.unibas.ch/61404/

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GABAB receptors (GABABRs) are considered promising drug targets for the treatment of mental health disorders. GABABRs are obligate heteromers of principal GABAB1 and GABAB2 subunits. GABABRs can additionally associate with auxiliary KCTD8, 12, 12b and 16 subunits, which also bind the G-protein and differentially regulate G-protein signaling. It is unknown whether the KCTDs allosterically influence pharmacological properties of GABABRs. Here we show that KCTD8 and KCTD16 slightly but significantly increase GABA affinity at recombinant receptors. However, KCTDs clearly do not account for the 10-fold higher GABA affinity of native compared to recombinant GABABRs. The positive allosteric modulator (PAM) GS39783, which binds to GABAB2, increases both potency and efficacy of GABA-mediated G-protein activation ([(35)S]GTPgammaS binding, BRET between G-protein subunits), irrespective of whether KCTDs are present or not. Of note, the increase in efficacy was significantly larger in the presence of KCTD8, which likely is the consequence of a reduced tonic G-protein activation in the combined presence of KCTD8 and GABABRs. We recorded Kir3 currents to study the effects of GS39783 on receptor-activated G-protein betagamma-signaling. In transfected CHO cells and cultured hippocampal neurons GS39783 increased Kir3 current amplitudes activated by 1 muM of baclofen in the absence and presence of KCTDs. Our data show that auxiliary KCTD subunits exert marginal allosteric influences on principal GABABR subunits. PAMs at principal subunits will therefore not be selective for receptor subtypes owing to KCTD subunits. However, PAMs can differentially modulate the responses of receptor subtypes because the KCTDs differentially regulate G-protein signaling.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Physiology > Molecular Neurobiology Synaptic Plasticity (Bettler)
UniBasel Contributors:Bettler, Bernhard
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1873-7064 (Electronic) 0028-3908 (Linking)
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:16 Oct 2018 16:44
Deposited On:16 Oct 2018 16:44

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