5-Hydroxytryptamine-induced contraction of human temporal arteries coexpressing 5-HT2A receptors and wild-type or variant (Phe124Cys) 5-HT1B receptors: increased contribution of 5-HT1B receptors to the total contractile amplitude in arteries from Phe124Cys heterozygous individuals.
OBJECTIVE
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.
Verheggen
Raphaela
R
Department of Neurosurgery, University of Göttingen, Göttingen, Germany.
Werner
Inga
I
Lücker
Anne
A
Brüss
Michael
M
Göthert
Manfred
M
Kaumann
Alberto J
AJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D014644:Genetic Variation / Q000502:physiology*; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects* / Q000235:genetics*; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology; D013699:Temporal Arteries / Q000187:drug effects* / Q000378:metabolism*
D044302:Receptor, Serotonin, 5-HT1B; D044402:Receptor, Serotonin, 5-HT2A; D012701:Serotonin; D018170:Sumatriptan