title: Adenosine A2A receptor induces protein kinase A-dependent functional modulation of human (alpha)3(beta)4 nicotinic receptor.
abstract: Adenosine modulates the function of nicotinic ACh receptors (nAChRs) in a variety of preparations, possibly through pathways involving protein kinase A (PKA), but these phenomena have not yet been investigated in detail. In this work we studied, using the patch clamp technique, the functional modulation of recombinant human α3β4 nAChR by the A2A adenosine receptor, co-expressed in HEK cells. Tonic activation of A2A receptor slowed current decay during prolonged applications of nicotine and accelerated receptor recovery from desensitization. Together, these changes resulted into a more sustained current response upon multiple nicotine or ACh applications. These findings were confirmed in cultured mouse superior cervical ganglion neurones, which express nAChR containing the α3 subunit together with β2 and/or β4 and A2A receptor. Expression of the A2A receptor in HEK cells also increased the apparent potency of nAChR for nicotine, further supporting a general A2A-induced gain of function for nAChR. These effects were dependent on PKA since the direct activation of PKA mimicked, and its inhibition prevented almost completely, the effects of the A2A receptor. Mutations of R385 and S388 in the cytoplasmic loop of the α3 subunit abolished the functional modulation of nAChR induced by activation of A2A receptor, PKA and other Ser/Thr kinases, suggesting that this region constitutes a putative consensus site for these kinases. These data provide conclusive evidence that activation of the A2A receptor determines functional changes
authors.affiliation: Dipartimento di Fisiologia e Farmacologia, Università Sapienza, P.le A. Moro 5; I-00185 Roma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Di Angelantonio
authors.forename: Alessio
authors.initials: A
authors.lastname: Piccioni
authors.forename: Claudia
authors.initials: C
authors.lastname: Moriconi
authors.forename: Flavia
authors.initials: F
authors.lastname: Trettel
authors.forename: Gloria
authors.initials: G
authors.lastname: Cristalli
authors.forename: Francesca
authors.initials: F
authors.lastname: Grassi
authors.forename: Cristina
authors.initials: C
authors.lastname: Limatola
mesh_terms: D015762:2-Chloroadenosine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000109:Acetylcholine / Q000502:physiology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000494:pharmacology; D019943:Amino Acid Substitution / Q000502:physiology; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009538:Nicotine / Q000494:pharmacology; D010766:Phosphorylation / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D017783:Superior Cervical Ganglion / Q000166:cytology; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D002227:Carbazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D043705:Receptor, Adenosine A2A; D011978:Receptors, Nicotinic; D014230:Triazoles; C403530:nicotinic receptor alpha3beta4; D015762:2-Chloroadenosine; D015124:8-Bromo Cyclic Adenosine Monophosphate; C057416:KT 5720; D009538:Nicotine; D017346:Protein Serine-Threonine Kinases; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; D017868:Cyclic AMP-Dependent Protein Kinases; D000243:Adenosine Deaminase; D000109:Acetylcholine