title: Cross-regulation between colocalized nicotinic acetylcholine and 5-HT3 serotonin receptors on presynaptic nerve terminals.
abstract: OBJECTIVE
  Substantial colocalization of functionally independent alpha4 nicotinic acetylcholine receptors and 5-HT(3) serotonin receptors on presynaptic terminals has been observed in brain. The present study was aimed at addressing whether nicotinic acetylcholine receptors and 5-HT(3) serotonin receptors interact on the same presynaptic terminal, suggesting a convergence of cholinergic and serotonergic regulation.
  
  
  METHODS
  Ca(2+) responses in individual, isolated nerve endings purified from rat striatum were measured using confocal imaging.
  
  
  RESULTS
  Application of 500 nmol/L nicotine following sustained stimulation with the highly selective 5-HT(3) receptor agonist m-chlorophenylbiguanide at 100 nmol/L resulted in markedly reduced Ca(2+) responses (28% of control) in only those striatal nerve endings that originally responded to m-chlorophenylbiguanide. The cross-regulation developed over several minutes. Presynaptic nerve endings that had not responded to m-chlorophenylbiguanide, indicating that 5-HT(3) receptors were not present, displayed typical responses to nicotine. Application of m-chlorophenylbiguanide following sustained stimulation with nicotine resulted in partially attenuated Ca(2+) responses (49% of control). Application of m-chlorophenylbiguanide following sustained stimulation with m-chlorophenylbiguanide also resulted in a strong attenuation of Ca(2+) responses (12% of control), whereas nicotine-induced Ca(2+) responses following sustained stimulation with nicotine were not significantly different from control.
  
  
  CONCLUSIONS
  These results indicate that the presynaptic Ca(2+) increases evoked by either 5-HT(3) receptor or nicotinic acetylcholine receptor activation regulate subsequent responses to 5-HT(3) receptor activation, but that only 5-HT(3) receptors cross-regulate subsequent nicotinic acetylcholine receptor-mediated responses. The findings suggest a specific interaction between the two receptor systems in the same striatal nerve terminal, likely involving Ca(2+)-dependent intracellular pathways that regulate these signaling systems at one or more levels.
authors.affiliation: Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Dougherty
authors.forename: Robert A
authors.initials: RA
authors.lastname: Nichols
mesh_terms: D000818:Animals; D001645:Biguanides / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D001645:Biguanides; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D044406:Receptors, Serotonin, 5-HT3; D017366:Serotonin Receptor Agonists; D009538:Nicotine; C065734:1-(3-chlorophenyl)biguanide; D002118:Calcium