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 (> or =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 pK(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.
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Endocrinology and Reproduction Research Group, GKT School of Biomedical Science, King's College London, London, SE1 1UL.
Sugden
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D000465:Algorithms; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000378:metabolism*; D066298:In Vitro Techniques; D008547:Melanophores / Q000378:metabolism*; D020460:Melanosomes / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology; D010860:Pigments, Biological / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D011985:Receptors, Serotonin / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D014982:Xenopus laevis
D000975:Antioxidants; D010860:Pigments, Biological; D012333:RNA, Messenger; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; D012701:Serotonin; D000242:Cyclic AMP; D008550:Melatonin