The involvement of GABAB receptors and coupled G-proteins in spinal GABAergic presynaptic inhibition

Abstract

GABA acts as a presynaptic inhibitory transmitter in the spinal cord. In the lamprey, it has recently been shown that it acts in this way at both primary sensory and motor system synapses and is important in the generation of a locomotor rhythm. Both GABAA and GABAB receptors are activated at these sites by GABA released during physiological activity. In some systems, GABAB receptor activation has been shown to lead to modulation of ion channel function indirectly through the action of a pertussis toxin (PTX)-sensitive G-protein. Here we have studied the mechanism of action of the presynaptic GABAB receptor in this system. GABAB receptor activation leads to a decrease in axonal membrane impedance and also to a reduction in the axonal action potential duration. The ionic basis for this response remains unknown, though it is not, unlike the response to GABAA receptor activation, mediated by an increase in conductance to Cl-. The effects of GABAB receptor antagonism with phaclofen are mimicked by pretreatment of the spinal cord with PTX. Because this procedure inactivates certain classes of G-proteins, it seemed likely that the GABAB receptor- mediated effects are initiated via a presynaptic population of PTX- sensitive G-proteins. Experiments in which only presynaptic G-proteins were interfered with indicate that this is so. Stable analogs of GTP and GDP were used to activate permanently or to antagonize, respectively, the GTP binding site in the presynaptic component of these spinal synapses. We conclude that GABAB receptor-mediated synaptic suppression in the spinal cord is caused by GTP binding to presynaptic G-proteins linked to the GABAB receptor.(ABSTRACT TRUNCATED AT 250 WORDS)