title: Effects of antihistamines on the function of human α7-nicotinic acetylcholine receptors.
abstract: Effects of the histamine H₁ receptor (H1R) antagonists (antihistamines), promethazine (PMZ), orphenadrine (ORP), chlorpheniramine (CLP), pyrilamine (PYR), diphenhydramine (DPH), citerizine (CTZ), and triprolidine (TRP) on the functional properties of the cloned α7 subunit of the human nicotinic acetylcholine receptor expressed in Xenopus oocytes were investigated. Antihistamines inhibited the α7-nicotinic acetylcholine receptor in the order PYR>CLP>TRP>PMZ>ORP≥DPH≥CTZ. Among the antihistamines, PYR showed the highest reversible inhibition of acetylcholine (100 µM)-induced responses with IC₅₀ of 6.2 µM. PYR-induced inhibition was independent of the membrane potential and could not be reversed by increasing the concentration of acetylcholine. Specific binding of [¹²⁵I] α-bungarotoxin, a selective antagonist for α7-nicotinic acetylcholine receptor, was not changed in the presence of PYR suggesting a non-competitive inhibition of nicotinic receptors. In line with functional experiments, docking studies indicated that PYR can potentially bind allosterically with the α7 transmembrane domain. Our results indicate that the H₂-H₄ receptor antagonists tested in this study (10 µM) showed negligible inhibition of α7-nicotinic acetylcholine receptors. On the other hand, H₁ receptor antagonists inhibited the function of human α7-nicotinic acetylcholine receptor, with varying potencies. These results emphasize the importance of α7-nicotinic acetylcholine receptor for future pharmacological/toxicological profiling.
authors.affiliation: Laboratory of Functional Lipidomics, Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, UAE University, Abu Dhabi, Al Ain, United Arab Emirates.
authors.forename: Bassem
authors.initials: B
authors.lastname: Sadek
authors.affiliation: Laboratory of Functional Lipidomics, Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, UAE University, Abu Dhabi, Al Ain, United Arab Emirates.
authors.forename: Seyedeh Soha
authors.initials: SS
authors.lastname: Khanian
authors.affiliation: Laboratory of Functional Lipidomics, Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, UAE University, Abu Dhabi, Al Ain, United Arab Emirates.
authors.forename: Abrar
authors.initials: A
authors.lastname: Ashoor
authors.affiliation: Department of Biological Sciences, Schmid College of Science and Technology, Chapman University, One University Drive, Orange, CA 92866, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Prytkova
authors.affiliation: College of Pharmacy, Al Ain University of Science and Technology, Al Ain, United Arab Emirates.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Ghattas
authors.affiliation: College of Pharmacy, Al Ain University of Science and Technology, Al Ain, United Arab Emirates.
authors.forename: Noor
authors.initials: N
authors.lastname: Atatreh
authors.affiliation: Laboratory of Functional Lipidomics, Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, UAE University, Abu Dhabi, Al Ain, United Arab Emirates.
authors.forename: Syed M
authors.initials: SM
authors.lastname: Nurulain
authors.affiliation: Department of Biological Sciences, Schmid College of Science and Technology, Chapman University, One University Drive, Orange, CA 92866, USA.
authors.forename: Keun-Hang Susan
authors.initials: KH
authors.lastname: Yang
authors.affiliation: Department of Physiology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
authors.forename: Frank Christopher
authors.initials: FC
authors.lastname: Howarth
authors.affiliation: Laboratory of Functional Lipidomics, Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, UAE University, Abu Dhabi, Al Ain, United Arab Emirates. Electronic address: Murat_Oz@uaeu.ac.ae.
authors.forename: Murat
authors.initials: M
authors.lastname: Oz
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D006634:Histamine H1 Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006635:Histamine H2 Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D054828:Histamine H3 Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007649:Ketamine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011738:Pyrilamine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C579167:Chrna7 protein, human; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D054828:Histamine H3 Antagonists; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D064569:alpha7 Nicotinic Acetylcholine Receptor; D007649:Ketamine; D011738:Pyrilamine
keywords: Antihistamine; Nicotinic acetylcholine receptor; Pyrilamine; Xenopus oocyte