Interactions between tachykinins and diverse, human nicotinic acetylcholine receptor subtypes.
Nicotinic acetylcholine receptors (nAChR) are diverse members of the ligand-gated ion channel superfamily of neurotransmitter receptors and play critical roles in chemical signaling throughout the nervous system. Reports of effects of substance P (SP) on nAChR function prompted us to investigate interactions between several tachykinins and human nAChR subtypes using clonal cell lines as simple experimental models. Acute exposure to SP inhibits carbamylcholine- or nicotine-stimulated function measured using 86Rb+ efflux assays of human ganglionic (alpha 3 beta 4) nAChR expressed in SH-SY5Y neuroblastoma cells (IC50 approximately 2.3 microM) or of human muscle-type (alpha 1 beta 1 gamma delta) nAChR expressed in TE671/RD clonal cells (IC50 approximately 21 microM). SP also acutely blocks function of rat ganglionic nAChR expressed in PC12 pheochromocytoma cells (IC50 approximately 2.1 microM). Neurokinin A and eledoisin inhibit function (extrapolated IC50 values between 60 and 160 microM) of human muscle-type or ganglionic nAChR, but neurokinin B does not, and neither human nAChR is as sensitive as PC12 cell alpha 3 beta 4-nAChR to eledoisin or neurokinin A inhibition. At concentrations that produce blockade of nAChR function, SP fails to affect binding of [3H]acetylcholine to human muscle-type or ganglionic nAChR. SP-mediated blockade of rat or human ganglionic nAChR function is insurmountable by increasing agonist concentrations. Collectively, these results indicate that tachykinins act noncompetitively to inhibit human nAChR function with potencies that vary across tachykinins and nAChR subtypes. They also indicate that tachykinin actions at nAChR could further contribute to complex cross-talk between nicotinic cholinergic and tachykinin signals in regulation of nervous system activity.
Lukas
R J
RJ
Division of Neurobiology, Barrow Neurological Institute, Phoenix, Arizona 85013, USA. RLUKAS@MHA.CHW.EDU
Eisenhour
C M
CM
D000818:Animals; D002999:Clone Cells / Q000378:metabolism; D005725:Ganglia, Autonomic / Q000378:metabolism; D006801:Humans; D016015:Logistic Models; D009132:Muscles / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015320:Tachykinins / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D011978:Receptors, Nicotinic; D015320:Tachykinins