Kinetic properties and regulation of GABAA receptor channels.

Single-channel recordings of GABAA receptor single-channel currents have been obtained from mouse spinal cord neurons in cell culture. Detailed kinetic analysis of single-channel main-conductance level currents has allowed development of a preliminary kinetic scheme which describes the gating of the GABAA receptor channel. The essential features of this kinetic scheme are presented in scheme 1 (see above). In this scheme, the GABAA receptor channel is envisioned to exist in multiple open and closed states. Properties can be broken into three main categories. First, the receptor can exist in a closed and nondesensitized set of states. In the kinetic model it is envisioned that there is an unbound (C13), a singly bound (C12), and two doubly bound (C11 and C10) closed states. The singly bound and doubly bound closed states are thought to open to three open states (O1, O2, O3). However, each of the open states opens to two distal closed states whose kinetic properties are similar for all three open states (C4-C9). Only one desensitized state (D0) has been incorporated into the model. While this characterization of desensitization is certainly incomplete, it is an initial step toward including the desensitization process which is clearly evident in whole-cell and single-channel recordings. This kinetic scheme should be considered only an initial working model. A number of features appear to be correct. First, all analyses of open time frequency histograms for GABA- and GABA agonist-induced single-channel openings have demonstrated the presence of at least three distinct open time constants. Furthermore, the concentration-dependent change in the relative frequency of occurrence of the three open states suggests that the open states occur from singly and doubly bound forms of the receptor. Second, the presence of two brief closed states adjacent to the open states appears fairly secure. However, it should be noted that the kinetic analysis primarily suggests that each open state opens to two brief adjacent closed states in a concentration-independent manner. While we have indicated that these two closed states are distal to the three open states, the actual assignment of the location of these states is unclear. Another interpretation of these data is that there is only a single distal closed state and that the proximal, extraburst closed states have very brief durations that are similar to each other. What appears clear, however, is that the open states can close to either brief closed state.(ABSTRACT TRUNCATED AT 400 WORDS)