An endogenous 5-HT7 receptor mediates pigment granule dispersion in Xenopus laevis melanophores

1 Melatonin (5-methoxy N-acetyltryptamine) and serotonin (5-HT) exert rapid , but opposite effects on pigment granule distribution in Xenopus laevis me lanophores. Low concentrations of melatonin (10(-11)-10(-9) M) cause a dram atic perinuclear aggregation of the melanin-containing granules, while 5-HT (10(-8)-10(-5) M) disperses pigment granules throughout the cell. 2 The present study found that pharmacological doses of melatonin (greater than or equal to 10(-6) M) induced a time- and concentration-dependent pigm ent granule dispersion, which was mediated by an endogenous melanophore 5-H T receptor. 3 5-HT produced a concentration-dependent elevation of melanophore cyclic A MP, and 5-HT-induced dispersion was blocked by H89 (10(-4) M), an inhibitor of protein kinase A (PKA), but not by a PKC inhibitor (Ro 31-8220, 10(-5) M), indicating a vital role for cyclic AMP in 5-HT-induced dispersion. 4 5-HT-mediated dispersion was not blocked by antagonists selective for G(s )-coupled 5-HT4 (GR113808) or 5-HT6 (Ro 04-6790, Ro 63-0563, olanzepine) re ceptors, nor by 5-HT1-3 (pindolol, ketanserine, metoclopramide, MDL72222, t ropisetron) receptor antagonists, but was inhibited by a selective 5-HT7 re ceptor antagonist, DR4004, and other antagonists with a high affinity for 5 -HT7 receptors. The rank order of antagonist potency was: risperidone (mean pK(B) 7.82) > methiothepin (7.43) > DR4004 (6.92) > mesulergine (6.83) > m ethysergide (6.60) > [+/-]-sulpiride (5.81) > spiperone (5.52). The agonist potency order [mean pEC(50), 5-CT (8.68) > 5-HT (7.13) > 5-MT (6.94) > 8-O H-DPAT (4.79) > sumatriptan (<4)] was also consistent with an action on 5-H T7 receptors. 5 RT-PCR confirmed that melanophores express 5-HT7 receptor mRNA. The pigme nt dispersing effect of high melatonin concentrations in melanophores is mo st likely mediated by activation of 5-HT7 receptors. Conceivably some of th e effects attributed to pharmacological doses of melatonin in mammals may b e mediated by activation of 5-HT7 receptors.