L-AP4 inhibits calcium currents and synaptic transmission via a G-protein-coupled glutamate receptor.
The AP4 (2-amino-4-phosphonobutyrate) receptor is a presynaptic glutamate receptor that inhibits transmitter release via an unknown mechanism. We examined the action of L-AP4 on voltage-dependent calcium currents and excitatory synaptic transmission on cultured olfactory bulb neurons using whole-cell voltage-clamp methods. In neurons dialyzed with GTP, L-AP4 inhibited high-threshold calcium currents evoked in barium solutions. The inhibition was irreversible in the presence of GTP-gamma-S and blocked by removing intracellular Mg2+ or by preincubation with pertussis toxin (PTX), consistent with the involvement of a PTX-sensitive G-protein. Dialysis with staurosporine or buffering of intracellular calcium to pCa less than 8 did not block the action of L-AP4, suggesting that protein phosphorylation or release of intracellular calcium stores was not involved in calcium current inhibition under these experimental conditions. PTX also blocked the L-AP4-induced inhibition of monosynaptic EPSPs evoked by intracellular stimulation of cultured mitral cells. These results suggest that the presynaptic AP4 receptor is a G-protein-coupled glutamate receptor, and that inhibition of calcium influx by a membrane-delimited action of a G-protein may account for L-AP4-induced presynaptic inhibition.
Trombley
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Department of Biology, University of Oregon, Eugene 97403.
Westbrook
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D000596:Amino Acids / Q000494:pharmacology; D000613:Aminobutyrates / Q000494:pharmacology*; D000818:Animals; D001464:Barium / Q000037:antagonists & inhibitors / Q000502:physiology; D002118:Calcium / Q000037:antagonists & inhibitors / Q000502:physiology*; D002478:Cells, Cultured; D004056:Differential Threshold; D004553:Electric Conductivity; D019204:GTP-Binding Proteins / Q000378:metabolism*; D037342:Pertussis Toxin; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter / Q000502:physiology*; D013569:Synapses / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000596:Amino Acids; D000613:Aminobutyrates; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter; D010566:Virulence Factors, Bordetella; D001464:Barium; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; C012729:2-amino-4-phosphonobutyric acid; D002118:Calcium