Entropy as a factor in the binding of γ-aminobutyric acid and nipecotic acid to the γ-aminobutyric acid transport system

摘要

Nipecotic acid is one of the most potent competitive inhibitors and alternative substrates for the high-affinity γ-aminobutyric acid transport system in neurons, but the structural basis of this potency is unclear. Because γ-aminobutyrate is a highly flexible molecule in solution, it would be expected to lose rotational entropy upon binding to the transport system, a change which does not favor binding. Nipecotic acid, in contrast, is a much less flexible molecule, and one would expect the loss of conformational entropy upon binding to be smaller thus favoring the binding of nipecotic acid over γ-aminobutyric acid. To investigate this possibility, the thermodynamic parameters, ΔG°, ΔH°, and ΔS°, were determined for the binding of γ-aminobutyrate and nipecotic acid to the high affinity GABA transport system in synaptosomes. In keeping with expectations, the apparent entropy change for nipecotic acid binding (112±13 J·K−1) was more favorable than the apparent entropy change for γ-aminobutyric acid binding (61.3±6.6 J·K−1). The results suggest that restricted conformation per se is an important contributory factor to the affinity of nipecotic acid for the high-affinity transport system for