Isovaline does not activate GABA(B) receptor-coupled potassium currents in GABA(B) expressing AtT-20 cells and cultured rat hippocampal neurons.

Abstract

Isovaline is a non-proteinogenic amino acid that has analgesic properties. R-isovaline is a proposed agonist of the γ-aminobutyric acid type B (GABA(B)) receptor in the thalamus and peripheral tissue. Interestingly, the responses to R-isovaline differ from those of the canonical GABA(B) receptor agonist R-baclofen, warranting further investigation. Using whole cell recording techniques we explored isovaline actions on GABA(B) receptors coupled to rectifying K+ channels in cells of recombinant and native receptor preparations. In AtT-20 cells transfected with GABA(B) receptor subunits, bath application of the GABA(B) receptor agonists, GABA (1 μM) and R-baclofen (5 μM) produced inwardly rectifying currents that reversed approximately at the calculated reversal potential for K+ R- isovaline (50 μM to 1 mM) and S-isovaline (500 μM) did not evoke a current. R-isovaline applied either extracellularly (250 μM) or intracellularly (10 μM) did not alter responses to GABA at 1 μM. Co-administration of R-isovaline (250 μM) with a low concentration (10 nM) of GABA did not result in a response. In cultured rat hippocampal neurons that natively express GABA(B) receptors, R-baclofen (5 μM) induced GABA(B) receptor-dependent inward currents. Under the same conditions R-isovaline (1 or 50 μM) did not evoke a current or significantly alter R-baclofen-induced effects. Therefore, R-isovaline does not interact with recombinant or native GABA(B) receptors to open K+ channels in these preparations.