Evidence that guanosine triphosphate (GTP)-binding proteins control a synaptic response in brain: effect of pertussis toxin and GTP gamma S on the late inhibitory postsynaptic potential of hippocampal CA3 neurons.

These experiments show that a synaptic response in brain, namely, the late inhibitory postsynaptic potential (IPSP) of hippocampal CA3 neurons in the rat hippocampal slice, was blocked by 2 compounds affecting guanosine triphosphate (GTP)-binding proteins. The first of these compounds, pertussis toxin, an inactivator of several GTP-binding proteins (G-proteins), excluding the GTP-binding protein that stimulates adenylyl cyclase, was injected intrahippocampally. The second compound, GTP gamma S, a nonhydrolyzable analog of GTP, was injected directly into postsynaptic neurons via the recording electrode. An ADP-ribosylation assay verified that the pertussis toxin had modified a major portion of the hippocampal pertussis toxin substrates of approximately 40,000 apparent molecular weight. Each agent blocked the conductance associated with both the late IPSP and the response to baclofen, an agonist for a putative receptor mediating the late IPSP (GABAB). These compounds did not block the mossy fiber excitatory postsynaptic potential (EPSP), the GABAA-mediated early IPSP, or the response to the GABAA agonist 4,5,6,7-tetrahydroisoxazolo-(5,4-C)-pyridin-3-ol. It is possible that these measurements underestimated the degree of blockade of the specific potassium conductance of the late IPSP since at least a portion of the GTP-gamma S-insensitive response was not a potassium conductance at all. Rather, it was a response with a reversal potential some 30 mV positive to that of the late IPSP. On the basis of these experiments, I propose that the transmitter receptor of the late IPSP activates a potassium conductance via a G-protein that is sensitive to blockade by pertussis toxin and that GTP gamma S and baclofen activate a conductance that depends upon the same G-proteins and/or potassium channels as does the late IPSP.