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Identity of adenylyl cyclase isoform determines the G protein mediating chronic opioid‐induced adenylyl cyclase supersensitivity
Author(s) -
Ammer Hermann,
Christ Thomas E.
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.01188.x
Subject(s) - adenylyl cyclase , gs alpha subunit , g protein , chemistry , gene isoform , pertussis toxin , intracellular , receptor , camp dependent pathway , μ opioid receptor , signal transduction , opioid , medicine , endocrinology , pharmacology , biochemistry , biology , gene
To determine the intracellular signal transduction pathway responsible for the development of tolerance/dependence, the ability of G z α to substitute for pertussis toxin (PTX)‐sensitive G proteins in mediating adenylyl cyclase (AC) supersensitivity was examined in the presence of defined AC isoforms. In transiently µ‐opioid receptor (OR) transfected COS‐7 cells (endogenous inhibitory G proteins: G i α2, G i α3 and G z α), neither acute (1 µmol/L) nor chronic morphine treatment (1 µmol/L; 18 h) influenced intracellular cAMP production. Coexpression of the µ‐OR together with AC type V and VI fully restored the ability of morphine to acutely inhibit cAMP generation. Chronic morphine treatment further resulted in the development of tolerance/dependence, as assessed by desensitization of the acute inhibitory opioid effect (tolerance) as well as the induction of AC supersensitivity after drug withdrawal (dependence). Specific direction of µ‐OR signalling via G z α by both PTX treatment and G z α over‐expression had no effect on chronic morphine regulation of AC type V, but completely abolished the development of tolerance/dependence with AC type VI. Similar results were obtained in stably µ‐OR‐expressing HEK293 cells transiently cotransfected with G z α and either AC type V or VI. Coprecipitation studies further verified that G z α specifically binds to AC type V but not type VI. Taken together, these results demonstrate that in principle each of the OR‐activated G proteins per se is able to mediate AC supersensitivity. However, they also indicate that it is the molecular nature of AC isoform that selects and determines the OR‐activated G protein mediating tolerance/dependence.