ABSTRACT
OBJECTIVES: Expression studies of the rare Phe124Cys sequence variant of the human 5-HT1B receptor in HEK293 cells demonstrated that 5-hydroxytryptamine (5-HT) and sumatriptan had both three times higher binding affinity and agonist potency at the variant receptor than wild-type receptor. We examined whether in-vivo expression of the variant compared to the wild-type Phe/Phe genotype at codon 124 of the 5-HT1B receptor in human temporal arteries modifies their agonist-induced contraction. METHODS: Rings of arteries, coexpressing 5-HT1B and 5-HT2A receptors, from 98 patients undergoing neurosurgery were set up to measure contraction. Blood sample genotyping was performed by PCR using a mutagenic primer which induces a NheI restriction site in the Cys but not in the Phe allele. RESULTS: Three patients exhibited the Cys/Phe genotype, probably yielding coexpression of both the 124Phe and the 124Cys 5-HT1B receptors. In 95 Phe/Phe patients, exclusively the 124Phe receptor was expressed. The contractile potencies of 5-HT and sumatriptan were not significantly different in arteries from Cys/Phe or Phe/Phe individuals. The 5-HT1B receptor-selective antagonist SB224289 was five-fold more potent in blocking the effects of 5-HT in arteries from three Cys/Phe than from 30 Phe/Phe individuals (P < 0.03). The fraction of 5-HT effects via 5-HT1B receptors, related to the total contractile amplitude via 5-HT1B and 5-HT2A receptors, was enhanced from 0.42 +/- 0.03 in 88 Phe/Phe individuals to 0.75 +/- 0.10 in three Cys/Phe individuals (P < 0.05). CONCLUSIONS: Although the potency of 5-HT1B receptor agonists does not differ between arteries from Phe/Phe and Cys/Phe individuals, the contribution of 5-HT1B receptors to the mediation of the effects of 5-HT is increased in Cys/Phe individuals.