Figure 7.
The T686 mutations speed recovery by increasing the rate of resensitization. a, Diagram (left) and partial kinetic model (right) showing one possible sequence of transitions (red arrows) that occurs for a desensitized channel during recovery. Opening of the binding cleft determines the time course of recovery and precedes dissociation of glutamate and reassembly of the dimer interface. The T686 mutations speed recovery by increasing the value of the rate constant COd. b, The rate of resensitization determines the recovery time course, and the T686 mutations increase both this rate (γ1) and the rate at which closed channels open their binding domains (CO). In the partial kinetic models shown in a and b, red arrows indicate the two rate-determining steps during recovery. In the diagrams and models, blue arrows are unlikely transitions, and blue states (and the pale diagram states) are unlikely to be visited. c, Simulated (simu.) recovery time courses (smooth curves) for GluR2-wt and the T686S and T686A mutants predicted for glutamate (left) and quiqualate (right) from the model in Figure 6a and the rate constants in Table 2. The simulated curves were scaled to give the correct extent of recovery at the longest intervals tested experimentally. The curves are superimposed on the mean experimental data from Figure 5, c and f. d, Experimental (open squares) and simulated (filled triangles) peak-to-plateau current ratios for GluR2-wt and the T686 serine and alanine mutants for glutamate (left) and quiqualate (right).