Dose-conductance relationships for GABA agonists and the effect of uptake inhibitors in crayfish stretch receptor neurons.

The interaction of GABA (gamma-aminobutyric acid) and structurally-related compounds with postsynaptic GABA receptors was studied quantitatively by measuring receptor-mediated increases in membrane input conductance in isolated crayfish stretch receptor neurons (SRN). The following compounds, in order of decreasing potency, were effective agonists: muscimol greater than GABA greater than isoguvacine greater than (-)gamma-amino-beta-hydroxybutyric acid greater than beta-gu anidinopropionic acid greater than 3-aminopropanesulfonic acid greater than (+)gamma-amino-beta-hydroxybutyric acid greater than isonipecotic acid greater than THIP. A highly significant correlation was found between the log potencies for GABA agonists that were obtained in the SRN and those obtained in our laboratory using mammalian GABA receptor binding assays. Hill plot analyses of the log concentration-conductance data from the SRN indicated a Hill slope (nH) of approximately 2 for all agonists except GABA and guanidinopropionic acid (nH greater than 2), two compounds known to be actively accumulated by cellular GABA uptake processes. Nipecotic acid, guvacine, and L-alpha, beta-diaminopropionic acid, blockers of GABA uptake processes, had essentially no effect by themselves on the SRN membrane input conductance at concentrations up to 5 mM, however, they potentiated the effects of sub-maximal concentrations of GABA and decreased the steepness of the log concentration-conductance curve, and consequently nH, for GABA. The effects of muscimol, however, were not affected. When the influence of uptake processes was considered, it appeared that all agonists tested acted by the same cooperative mechanism which required at least two molecules of agonist to activate a receptor-ionophore unit.