An endogenous 5‐HT 7 receptor mediates pigment granule dispersion in Xenopus laevis melanophores

Melatonin (5‐methoxy N ‐acetyltryptamine) and serotonin (5‐HT) exert rapid, but opposite effects on pigment granule distribution in Xenopus laevis melanophores. Low concentrations of melatonin (10 −11  – 10 −9   M ) cause a dramatic perinuclear aggregation of the melanin‐containing granules, while 5‐HT (10 −8  – 10 −5   M ) disperses pigment granules throughout the cell. The present study found that pharmacological doses of melatonin (10 −6   M ) induced a time‐ and concentration‐dependent pigment granule dispersion, which was mediated by an endogenous melanophore 5‐HT receptor. 5‐HT produced a concentration‐dependent elevation of melanophore cyclic AMP, 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. 5‐HT‐mediated dispersion was not blocked by antagonists selective for G s ‐coupled 5‐HT 4 (GR113808) or 5‐HT 6 (Ro 04‐6790, Ro 63‐0563, olanzepine) receptors, nor by 5‐HT 1 – 3 (pindolol, ketanserine, metoclopramide, MDL72222, tropisetron) receptor antagonists, but was inhibited by a selective 5‐HT 7 receptor antagonist, DR4004, and other antagonists with a high affinity for 5‐HT 7 receptors. The rank order of antagonist potency was: risperidone (mean p K B 7.82)>methiothepin (7.43)>DR4004 (6.92)>mesulergine (6.83)>methysergide (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‐OH‐DPAT (4.79)>sumatriptan (<4)] was also consistent with an action on 5‐HT 7 receptors. RT – PCR confirmed that melanophores express 5‐HT 7 receptor mRNA. The pigment dispersing effect of high melatonin concentrations in melanophores is most likely mediated by activation of 5‐HT 7 receptors. Conceivably some of the effects attributed to pharmacological doses of melatonin in mammals may be mediated by activation of 5‐HT 7 receptors.British Journal of Pharmacology (2001) 132 , 1799–1808; doi: 10.1038/sj.bjp.0703988