Na(+)-dependent metabolic coupling upon 5-HT1B receptor activation by sumatriptan and related agonists

The efficacy of the antimigraine compound sumatriptan in migraine relief has been attributed to its interaction with 5-HT1B receptors in cerebral blood vessels causing cranial vasoconstriction, and/or on nerve endings of the trigeminovascular system in the dura mater inhibiting the inflammatory process by decreasing neuropeptide release. Otherwise, the metabolic effects following 5-HT1B receptor activation are largely unknown. In CHO-K1 cells expressing recombinant h5-HT1B receptors, activation of these receptors by sumatriptan and related agonists enhanced their metabolic rate by 34.9%, but not in wild-type cells. Treatment with pertussis toxin (100 ng/ml), addition of the 5-HT1B receptor antagonist GR127935 (30 nM), attenuation or substitution of the extracellular glucose supply, prevented the sumatriptan-mediated enhancement of the metabolic rate. This metabolic enhancement was also blocked by washout of extracellular Na+, independent of the blockade of the Na+/H+ antiporter by ethylisopropylamiloride. The Na(+)-dependent metabolic enhancement by sumatriptan suggests activated 5-HT1B receptors pilot cellular energy demand. This metabolic feature may contribute to the mode of action of 5-HT1B agonists in migraine relief.