A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
The Influence of AA29504 on GABA A Receptor Ligand Binding Properties and Its Implications on Subtype Selectivity
Tekijät: Sikstus Sylvia, Benkherouf Ali Y, Soini Sanna L, Uusi-Oukari Mikko
Julkaisuvuosi: 2022
Journal: Neurochemical Research
Tietokannassa oleva lehden nimi: Neurochemical research
Lehden akronyymi: Neurochem Res
Vuosikerta: 47
Numero: 3
Aloitussivu: 667
Lopetussivu: 678
ISSN: 0364-3190
eISSN: 1573-6903
DOI: https://doi.org/10.1007/s11064-021-03475-y
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/67564662
The unique pharmacological properties of δ-containing γ-aminobutyric acid type A receptors (δ-GABAARs) make them an attractive target for selective and persistent modulation of neuronal excitability. However, the availability of selective modulators targeting δ-GABAARs remains limited. AA29504 ([2-amino-4-(2,4,6-trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester), an analog of K+ channel opener retigabine, acts as an agonist and a positive allosteric modulator (Ago-PAM) of δ-GABAARs. Based on electrophysiological studies using recombinant receptors, AA29504 was found to be a more potent and effective agonist in δ-GABAARs than in γ2-GABAARs. In comparison, AA29504 positively modulated the activity of recombinant δ-GABAARs more effectively than γ2-GABAARs, with no significant differences in potency. The impact of AA29504's efficacy- and potency-associated GABAAR subtype selectivity on radioligand binding properties remain unexplored. Using [3H]4'-ethynyl-4-n-propylbicycloorthobenzoate ([3H]EBOB) binding assay, we found no difference in the modulatory potency of AA29504 on GABA- and THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol)-induced responses between native forebrain GABAARs of wild type and δ knock-out mice. In recombinant receptors expressed in HEK293 cells, AA29504 showed higher efficacy on δ- than γ2-GABAARs in the GABA-independent displacement of [3H]EBOB binding. Interestingly, AA29504 showed a concentration-dependent stimulation of [3H]muscimol binding to γ2-GABAARs, which was absent in δ-GABAARs. This was explained by AA29504 shifting the low-affinity γ2-GABAAR towards a higher affinity desensitized state, thereby rising new sites capable of binding GABAAR agonists with low nanomolar affinity. Hence, the potential of AA29504 to act as a desensitization-modifying allosteric modulator of γ2-GABAARs deserves further investigation for its promising influence on shaping efficacy, duration and plasticity of GABAAR synaptic responses.
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