Differential desensitization of responses mediated by presynaptic and postsynaptic A1 adenosine receptors.
G-protein-coupled receptors (GPCRs) often desensitize during continuous activation, but it is not known whether desensitization is influenced by subcellular location. In hippocampal neurons, activation of adenosine A1 receptors (A1Rs) or GABA(B) receptors on synaptic terminals inhibits neurotransmitter release, whereas activation of the same receptors on cell bodies and dendrites decreases excitability by activating inwardly rectifying potassium (GIRK) channels. Here we report that responses mediated by presynaptic A1Rs desensitize more slowly than responses mediated by postsynaptic (somatodendritic) A1Rs in cultured neurons. Agonist treatment for 2 hr has no effect on adenosine-induced presynaptic inhibition, whereas such treatment nearly abolishes adenosine-induced activation of postsynaptic GIRK channels. Agonist treatment for longer periods (>12 hr) eventually desensitizes A1R-mediated presynaptic inhibition. Presynaptic and postsynaptic responses both recover from desensitization after agonist removal, but recovery of presynaptic inhibition requires more time. Desensitization of postsynaptic responses apparently occurs at the level of the receptor, because postsynaptic G-proteins and GIRK channels appear to be fully functional. Inhibition of voltage-gated calcium channels by postsynaptic A1Rs also desensitizes rapidly, although this desensitization is less complete than is observed for activation of postsynaptic GIRK channels. Comparison of concentration-response curves for presynaptic and postsynaptic responses suggests that a receptor reserve exists for presynaptic inhibition, but that the magnitude of this reserve is insufficient to account for the absence of presynaptic desensitization after brief agonist exposure. These results suggest that agonist-induced desensitization of responses mediated by neuronal GPCRs may depend on the subcellular location of the receptors.
Wetherington
Jonathon P
JP
Department of Pharmacology and Toxicology, Medical College of Georgia, and Medical Research Service, Augusta Veterans Affairs Medical Center, Augusta, Georgia 30912, USA.
Lambert
Nevin A
NA
D015762:2-Chloroadenosine / Q000494:pharmacology; D000200:Action Potentials / Q000502:physiology; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D019204:GTP-Binding Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D014970:Xanthines / Q000494:pharmacology
D015220:Calcium Channels; D018755:GABA Agonists; D018756:GABA Antagonists; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D015221:Potassium Channels; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014970:Xanthines; D015762:2-Chloroadenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D019204:GTP-Binding Proteins; D000241:Adenosine