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The role of loop F residues in determining differential d-tubocurarine potencies in mouse and human 5-hydroxytryptamine 3A receptors
Journal article   Peer reviewed

The role of loop F residues in determining differential d-tubocurarine potencies in mouse and human 5-hydroxytryptamine 3A receptors

Ran Zhang, Xiaofei Wen, Julius Militante, Brent Hester, Heather E Rhubottom, Hongwei Sun, Nancy J Leidenheimer, Dong Yan, Michael M White and Tina K Machu
Biochemistry (Easton), v 46(5), pp 1194-1204
06 Feb 2007
DOI: https://doi.org/10.1021/bi0616100
PMID: 17260949
Featured in Collection :   UN Sustainable Development Goals @ Drexel

Abstract

Xenopus Transduction, Genetic Species Specificity Humans Receptors, Serotonin - drug effects Electrophysiology Binding Sites - genetics Receptors, Serotonin - genetics Amino Acids Oocytes Neuromuscular Nondepolarizing Agents - pharmacology Point Mutation Receptors, Serotonin, 5-HT3 Tubocurarine - pharmacology Animals Inhibitory Concentration 50 Mice
The competitive antagonist d-tubocurarine (curare) has greater potency at mouse than at human 5-hydroxytryptamine 3A (5-HT3A) receptors, despite 84% amino acid sequence identity between the receptors. Within the ligand binding domain of this receptor are six loops (A-F). A previous report demonstrated that loop C of the 5-HT3A receptor contributed to differential potency between the receptors [Hope, A. G. et al. (1999) Mol. Pharmacol. 55, 1037-1043]. The present study tested the hypothesis that loop F plays a significant role in conferring interspecies curare potency differences. Wild-type, chimeric, and point mutant 5-HT3A receptors were expressed in Xenopus oocytes, and two-electrode voltage clamp electrophysiological recordings were performed. Our data suggest that loops C and F contribute to curare potency, given that the curare IC50's (concentration of drug that produces 50% inhibition of the response) for chimeric human receptors with substitutions of mouse residues in loop C (40.07 +/- 2.52 nM) or loop F (131.8 +/- 5.95 nM) were intermediate between those for the mouse (12.99 +/- 0.77 nM) and human (1817 +/- 92.36 nM) wild-type receptors. Two human point mutant receptors containing mouse receptor substitutions in loop F (H-K195E or H-V202I) had significantly lower curare IC50's than that of the human receptor. The human double mutant receptor, H-K195E,V202I, had the same curare IC50 (133.8 +/- 6.38 nM) as that of the human receptor containing all six loop F mouse substitutions. These results demonstrate that two loop F residues make a significant contribution in determining curare potency at the 5-HT3A receptor.

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Collaboration types
Domestic collaboration
Web of Science research areas
Biochemistry & Molecular Biology
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