TAILIEUCHUNG - Báo cáo khoa học: Activation of the Torpedo nicotinic acetylcholine receptor The contribution of residues aArg55 and cGlu93

TheTorpedonicotinic acetylcholine receptor is a heteropentamer (a2bcd)in which structurally homologous subunits assemble to form a central ion pore. Viewed from the synaptic cleft, the likely arrangement of these sub-units isa–c–a–d–blying in an anticlockwise orientation. | iFEBS Journal Activation of the Torpedo nicotinic acetylcholine receptor The contribution of residues aArg55 and cGlu93 Ankur Kapur Martin Davies William F. Dryden and Susan . Dunn Department of Pharmacology Faculty of Medicine and Dentistry University of Alberta Edmonton Canada Keywords acetylcholine loop D mutagenesis nicotinic receptor oocytes Correspondence . Dunn Department of Pharmacology University of Alberta Edmonton Alberta T6G 2H7 Canada Fax 780 4924325 Tel 780 4923414 E-mail Received 22 October 2005 revised 13 December 2005 accepted 23 December 2005 doi The Torpedo nicotinic acetylcholine receptor is a heteropentamer a2PyS in which structurally homologous subunits assemble to form a central ion pore. Viewed from the synaptic cleft the likely arrangement of these subunits is a-y-a-S-P lying in an anticlockwise orientation. High affinity binding sites for agonists and competitive antagonists have been localized to the a-y and a-S subunit interfaces. We investigated the involvement of amino acids lying at an adjacent interface y-a in receptor properties. Recombinant Torpedo receptors expressed in Xenopus oocytes were used to investigate the consequences of mutating aArg55 and yGlu93 residues that are conserved in most species of the peripheral nicotinic receptors. Based on homology modeling these residues are predicted to lie in close proximity to one another and it has been suggested that they may form a salt bridge in the receptor s three-dimensional structure Sine et al. 2002 J Biol Chem 277 29 210-29 223 . Although substitution of aR55 by phenylalanine or tryptophan resulted in approximately a six-fold increase in the EC50 value for acetylcholine activation the charge reversal mutation aR55E had no significant effect. In contrast the replacement of yE93 by an arginine conferred an eight-fold increase in the potency for acetylcholine-induced receptor activation. In the receptor carrying the

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