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

Abstract

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.

Differential GABAB Receptor Modulation of Ethanol Effects on GABAA Synaptic Activity in Hippocampal CA1 Neurons

“…Evidence for a postsynaptic GABA B receptor-mediated IPSC has been shown in hippocampal neurons (Thalmann, 1988). This late inhibitory postsynaptic potential was mediated by pertussis toxin-sensitive, G protein-mediated activation of G protein-coupled inwardly rectifying potassium channels and inhibition of N-type Ca 2ϩ channels (Bertrand et al, 2003).…”

Synaptic Depolarizing GABA Response in Adults Is Excitatory and Proconvulsive When GABAB Receptors Are Blocked

“…CGP may lengthen the epileptiform event either by blocking the depressive effect of GABA on glutamate release, which is mediated by GABA B receptors on glutamatergic terminals (Isaacson et al 1993), or by a reduction in postsynaptic GABA B -mediated inhibition (Dutar and Nicoll 1988;Newberry and Nicoll 1985;Thalmann 1988b). One or both of these mechanisms have been suggested to be involved in the enhancement of epileptiform discharges caused by GABA B receptor antagonist in other models of epileptiform activity (Badran et al 1997;Huszár and Merlin 2004;McLean et al 1996;Scanziani et al 1994;Sutor and Luhmann 1998).…”

Synthesis of models for excitable membranes, synaptic transmission and neuromodulation using a common kinetic formalism

“…Figure 8 shows an implementation of the G-protein kinetic scheme, with the time course of the different protein species during the release of transmitter. The case of the GABA~-mediated current was chosen here because its kinetics have been characterized (Otis et al, 1993) and there is strong evidence that direct G-protein binding mediates the gating process Kinetic Models of Ion Channels 215 (Andrade et al, 1986;Thalmann, 1988;Brown and Birnbaumer, 1990). In the model illustrated in Fig.…”