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Kinetics of recovery from opioids at wild‐type and mutant μ opioid receptors expressed in Xenopus oocytes
Author(s) -
Spivak Charles E.,
Beglan Carol L.
Publication year - 2000
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/1098-2396(20001201)38:3<254::aid-syn4>3.0.co;2-9
Subject(s) - agonist , receptor , xenopus , chemistry , μ opioid receptor , pharmacology , opioid , mutant , antagonist , biophysics , biology , microbiology and biotechnology , biochemistry , gene
To investigate a previous observation that classical antagonists behave as agonists at mutant H297N and H297Q μ opioid receptors, we compared the kinetics of recovery from opioids at wild‐type and mutant μ receptors expressed in voltage‐clamped Xenopus oocytes. The cDNA for the potassium channel GIRK1 was coinjected into the oocytes with that of the μ receptors to transduce agonist binding into a coupled electrophysiological response. The kinetics of recovery were estimated by brief test pulses of the agonist normorphine given at a frequency of 0.67 or 1 per min. After treatment with a variety of agonists, the receptors recovered from desensitization at rates that depended on the agonist, but there was little difference between mutant and wild‐type receptors. Antagonists, however, induced agonist‐like currents and demonstrated faster recovery at the mutant receptors. These results suggest that His‐297 may comprise part of an antagonist subsite. This conclusion, when coupled with the steric theory that intrinsic activity depends on independent binary equilibration of a drug between agonist and antagonist subsites, could unify the paired observations that antagonists become agonists and recover faster at the mutant than at the wild‐type receptors. Synapse 38:254–260, 2000. Published 2000 Wiley‐Liss, Inc.