SEQUENCE AND FUNCTIONAL-ANALYSIS OF CLONED GUINEA-PIG AND RAT SEROTONIN 5-HT1D RECEPTORS, COMMON PHARMACOLOGICAL FEATURES WITHIN THE 5-HT1DRECEPTOR SUBFAMILY

This study was undertaken to investigate the pharmacology of cloned gu inea pig and rat 5-hydroxytryptamine (serotonin; 5-HT)(1D) receptor si tes. Guinea pig, rat, and mouse 5-HT1D receptor genes were cloned, and their amino acid sequences were compared with those of the human, dog , and rabbit, The overall amino acid sequence identity between these 5 -HT1D receptors is high and varies between 86 and 99%, The sequence ho mology is slightly more divergent (13-27%) in the N-terminal extracell ular region of these 5-HT1D receptors, Guinea pig and rat 5-HT1D recep tors, stably and separately expressed in rat C6 glial cells, are negat ively coupled to cyclic AMP formation upon stimulation with agonists, as previously found for cloned human 5-HT1D receptor sites. The cyclic AMP data show some common pharmacological features for the 5-HT1D rec eptors of guinea pig, rat, and human: an almost similar rank order of potency for the investigated 5-HT1D receptor agonists, stereoselectivi ty for the binding affinity and agonist potency of R(+)-8-hydroxy-2-(d i-n-propylamino) tetralin, and equal 5-HT1D receptor-mediated antagoni st potency for methiothepin and the 5-HT2 receptor antagonists ritanse rin and ketanserin. In conclusion, the pharmacology of the cloned 5-HT 1D receptor subtype seems, unlike the 5-HT1B receptor subtype, conserv ed among various mammal species such as the human, guinea pig, and rat .