Real‐time analysis of dopamine: antagonist interactions at recombinant human D 2long  receptor upon modulation of its activation state | Zendy

Pauwels Petrus J | Zendy; Tardif Stéphanie | Zendy; Wurch Thierry | Zendy; Colpaert Francis C | Zendy

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Real‐time analysis of dopamine: antagonist interactions at recombinant human D 2long receptor upon modulation of its activation state

Author(s) -

Pauwels Petrus J,

Tardif Stéphanie,

Wurch Thierry,

Colpaert Francis C

Publication year - 2001

Publication title -

british journal of pharmacology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.432

H-Index - 211

eISSN - 1476-5381

pISSN - 0007-1188

DOI - 10.1038/sj.bjp.0704243

Subject(s) - receptor , dopamine receptor d2 , agonist , chemistry , dopamine receptor , partial agonist , dopamine , receptor antagonist , antagonist , intrinsic activity , dopamine antagonist , endogenous agonist , competitive antagonist , dopamine receptor d3 , haloperidol , dopamine receptor d1 , pharmacology , endocrinology , biology , biochemistry

Antipsychotic drugs may mediate their therapeutic effects not only by preventing the binding of dopamine but also by decreasing the propensity of the dopamine receptor to assume an active R* state. Ligand‐mediated activation and blockade of the recombinant human D 2long receptor was investigated in CHO‐K1 cells upon modulation of its R* state. Both the Ala 371 Lys (A371K) and Thr 372 Arg (T372R) D 2long receptor mutants could be activated in a ligand‐dependent manner via a chimeric G αq/o protein, and more efficaciously so than with the promiscuous G α15 protein. Dopamine and partial agonists (E max : lisuride>>(+)‐UH 232≃bromerguride) displayed dissimilar Ca 2+ kinetic properties at wild‐type and mutant receptors. A371K and T372R D 2long receptor mutants demonstrated an attenuated and enhanced maximal response to these partial agonists, respectively. Dopamine antagonists were unable to block the transient high‐magnitude Ca 2+ phase at the wild‐type D 2long receptor upon simultaneous exposure to antagonist and dopamine, while full blockade of the low‐magnitude Ca 2+ phase did occur at a later time (onset‐time: haloperidol

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