D2 receptors inhibit the secretory process downstream from calcium influx in dopaminergic neurons: implication of K+ channels.
Dopaminergic (DAergic) neurons possess D2-like somatodendritic and terminal autoreceptors that modulate cellular excitability and dopamine (DA) release. The cellular and molecular processes underlying the rapid presynaptic inhibition of DA release by D2 receptors remain unclear. Using a culture system in which isolated DAergic neurons establish self-innervating synapses ("autapses") that release both DA and glutamate, we studied the mechanism by which presynaptic D2 receptors inhibit glutamate-mediated excitatory postsynaptic currents (EPSCs). Action-potential evoked EPSCs were reversibly inhibited by quinpirole, a selective D2 receptor agonist. This inhibition was slightly reduced by the inward rectifier K(+) channel blocker barium, largely prevented by the voltage-dependent K(+) channel blocker 4-aminopyridine, and completely blocked by their combined application. The lack of a residual inhibition of EPSCs under these conditions argues against the implication of a direct inhibition of presynaptic Ca(2+) channels. To evaluate the possibility of a direct inhibition of the secretory process, spontaneous miniature EPSCs were evoked by the Ca(2+) ionophore ionomycin. Ionomycin-evoked release was insensitive to cadmium and dramatically reduced by quinpirole, providing evidence for a direct inhibition of quantal release at a step downstream to Ca(2+) influx through voltage-dependent Ca(2+) channels. Surprisingly, this effect of quinpirole on ionomycin-evoked release was blocked by 4-aminopyridine. These results suggest that D2 receptor activation decreases neurotransmitter release from DAergic neurons through a presynaptic mechanism in which K(+) channels directly inhibit the secretory process.
Congar
Patrice
P
Départements de Pharmacologie et de Psychiatrie, Centre de Recherche en Sciences Neurologiques, Centre de Recherche Fernand Seguin, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Quebec H3C 3J7, Canada.
Bergevin
Annie
A
Trudeau
Louis-Eric
LE
D015761:4-Aminopyridine / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001464:Barium / Q000494:pharmacology; D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D004298:Dopamine / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004546:Elapid Venoms / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000502:physiology; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D017661:Receptors, Presynaptic / Q000378:metabolism; D013469:Sulpiride / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000166:cytology*
D015220:Calcium Channels; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D004546:Elapid Venoms; D018691:Excitatory Amino Acid Antagonists; D007476:Ionophores; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D017448:Receptors, Dopamine D2; D017661:Receptors, Presynaptic; D002104:Cadmium; D019257:Quinpirole; D001464:Barium; D018698:Glutamic Acid; D015759:Ionomycin; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C020273:dendrotoxin; D013469:Sulpiride; D015761:4-Aminopyridine; D002118:Calcium; D004298:Dopamine