How quickly can GABA_A receptors open?

We have examined GABA_A receptor activation by making rapid applications of GABA to outside-out patches excised from cultured postnatal rat cerebellar neurons. The rate of development of current increases with increasing GABA concentration from a low to a high concentration asymptote. The low concentration asymptote is about 10 s^-1 for patches taken from granule cells and 4 s^-1 for patches from Purkinje cells. The high concentration asymptote is about 6000 s^-1 for patches taken from either granule cells or Purkinje cells. The high concentration asymptote gives an estimate of the fastest rate at which these channels can open and indicates that agonist binding steps are not rate limiting. The concentration dependence of the development of current indicates that more than one GABA molecule is bound to most receptors with open channels and that the final binding step is of low affinity (about 500 μM). A comparison with GABA-mediated postsynaptic currents suggests that the properties of the GABA_A receptor play a major role in determining the shape of inhibitory synaptic responses and that the cleft concentration of GABA reaches at least 500 μM.