期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 278, 期 47, 页码 46583-46589出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M308974200
关键词
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Ligand- gated ion channels are integral membrane proteins that mediate fast synaptic transmission. Molecular biological techniques have been extensively used for determining the structure- function relationships of ligand- gated ion channels. However, the transduction mechanisms that link agonist binding to channel gating remain poorly understood. Arginine 222 ( Arg- 222), located at the distal end of the extracellular N- terminal domain immediately preceding the first transmembrane domain ( TM1), is conserved in all 5- HT3A receptors and alpha7- nicotinic acetylcholine receptors that have been cloned. To elucidate the possible role of Arg- 222 in the function of 5- HT3A receptors, we mutated the arginine residue to alanine ( Ala) and expressed both the wildtype and the mutant receptor in human embryonic kidney 293 cells. Functional studies of expressed wild- type and mutant receptors revealed that the R222A mutation increased the apparent potency of the full agonist, serotonin ( 5- HT), and the partial agonist, 2- Me- 5- HT, 5- and 12- fold, respectively. In addition, the mutation increased the efficacy of 2- Me- 5- HT and converted it from a partial agonist to a full agonist. Furthermore, this mutation also converted the 5- HT3 receptor antagonist/ very weak partial agonist, apomorphine, to a potent agonist. Kinetic analysis revealed that the R222A mutation increased the rate of receptor activation and desensitization but did not affect rate of deactivation. The results suggest that the pre- TM1 amino acid residue Arg- 222 may be involved in the transduction mechanism linking agonist binding to channel gating in 5- HT3A receptors.
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