Activation of the α1β2γ2L GABAA Receptor by Physiological Agonists

Abstract

The Cl^- permeable GABA_A receptor is a major contributor to cellular inhibition in the brain. The receptor is normally activated by synaptically-released or ambient GABA but is sensitive to a number of physiological compounds such as β-alanine, taurine, and neurosteroids that, to various degrees, activate the receptor and modulate responses either to the transmitter or to each other. Here, we describe α1β2γ2L GABA_A receptor activation and modulation by combinations of orthosteric and allosteric activators. The overall goal was to gain insight into how changes in the levels of endogenous agonists modulate receptor activity and influence cellular inhibition. Experimental observations and simulations are described in the framework of a cyclic concerted transition model. We also provide general analytical solutions for the analysis of electrophysiological data collected in the presence of combinations of active compounds.

Keywords: GABAA receptor; activation; allosteric agonist; orthosteric agonist; potentiation.

Figure 1

Agonist concentration-response relationships. The graphs show the probability of being in the active state (P_A) vs. the concentration of agonist. The curves in panel (A) were calculated using the K_R and c values provided in Table 1. The graph indicates that GABA, β-alanine, and taurine are high-efficacy agonists and the neurosteroids 3α5αP, 3α5βP, and etiocholanolone are low-efficacy agonists of the α1β2γ2L receptor. The concentration-response curves for the three steroids are shown at higher resolution in panel (D). Panels (B,C) show modulation of responses to GABA in the presence of 0.1, 1, or 10 mM β-alanine or taurine. While either compound is ineffective at 0.1 mM, potentiation of GABA responses is observed at 1 and 10 mM. Panel D shows activation of the receptor by 3α5αP, 3α5βP, or etiocholanolone, and combinations of 3α5αP or 3α5βP with 1 or 10 µM etiocholanolone. The presence of 10 but not 1 µM etiocholanolone reduces the response to 3α5αP or 3α5βP. Panels (E–G) show the effects of 3α5αP, 3α5βP, or etiocholanolone on GABA concentration-response curves. Strong potentiation of GABA responses is observed at 1 µM 3α5αP or 3α5βP.