Intracellular Cl⁻ accumulation reduces Cl⁻ conductance in inhibitory synaptic channels

Abstract

Glycine increases Cl⁻ conductance in neurones of the lamprey central nervous system and mimics the natural inhibitory transmitter pharmacologically^1,2. We have used current noise produced by glycine to examine in more detail the characteristics of inhibitory channels in Müller cells in the brain stem reticular formation. The channels have large conductances and mean open times consistent with large amplitudes and long durations of spontaneously occurring inhibitory synaptic currents³. We now show that, unlike any post-junctional channels reported so far, their conductance decreases rapidly with increasing intracellular concentration of the permeant ion. This surprising behaviour is inconsistent with constant field theory^4,5 and also with a single-site pore model such as proposed for cationic channels at the motor endplate⁶, both of which predict an increase in conductance with concentration. In addition, the decrease in conductance cannot be explained quantitatively by a two-site, single-file pore model such as proposed for K⁺ channels⁷ and Na⁺ channels⁸ in nerve and for gramicidin channels⁹. This property of the inhibitory channel may be functionally important in preventing intracellular Cl⁻ accumulation during periods of intense synaptic activity when inhibition might otherwise convert progressively to excitation as the Cl⁻ equilibrium potential became more and more positive.