Discussion

The crucial issues are whether or not melatonin and B-HT 920 share the same site within the cuckoo wrasse melanophore assay, and if this site is located on the a2-adrenoceptor or not.

Possible alternatives are an a2-adrenoceptor and an mtrreceptor and the two different types of receptors integrate the melatonin binding somewhere downstream of the receptors, i.e. the second messenger systems, the complex interactions between phosphatases and kinases that lead to an pigment aggregation, or along those proteins that participate in pigment migration. However, this model does not seem to be satisfactory considering that melatonin antagonizes B-HT 920 in innervated melanophores and that yohimbine is a potent antagonist against melatonin-induced pigment aggregation in denervated melanophores.

A highly speculative hypothesis is that there is a new type of a melatonin receptor, MT4. The criteria for this receptor would be i) affinity for yohimbine (which actually has an indol moiety), ii) affinity for the a2-adrenoceptor agonist B-HT 920, and iii) an increase in intracellular Ca2+ as a possible signal transduction mechanism. The idea is not supported by experimental data from other laboratories or in binding studies.

Pigment aggregation Pigment aggregation Pigment aggregation Pigment aggregation

Fig+ure 6. Four different hypotheses that could explain the diversity of the responses mediated by melatonin. The first suggests an a2-adrenoceptor that cooperates in an unknown way with a mt1-receptor. The second theory is a new unknown subtype of the melatonin receptor. A third possibility is that an unknown receptor protein mediates an increase in intracellular Ca2+ The fourth hypothesis indicates an a2-adrenoceptor with two functional sites.

Pigment aggregation Pigment aggregation Pigment aggregation Pigment aggregation

Fig+ure 6. Four different hypotheses that could explain the diversity of the responses mediated by melatonin. The first suggests an a2-adrenoceptor that cooperates in an unknown way with a mt1-receptor. The second theory is a new unknown subtype of the melatonin receptor. A third possibility is that an unknown receptor protein mediates an increase in intracellular Ca2+ The fourth hypothesis indicates an a2-adrenoceptor with two functional sites.

A third possibility is that pigment aggregation is mediated by different receptor proteins that have very similar active sites and recognize B-HT 920, but differentiate between noradrenaline and melatonin. There is, however, no report of such a receptor, perhaps due to the assumption that the a2-adrenoceptor agonists are highly selective for the presumed receptor type. Nonetheless, it should also be kept in mind that there are no investigations that have ruled out B-HT 920 as a melatonin ligand.

One hypothesis that remains, is the idea of an a2-adrenoceptor with two active sites, the two-site model. Depending on affinity and efficacy of the ligand that binds to one of the two sites, the response could vary in many ways. Moreover, if a neurotransmitter and a hormone can be influence the cellular response by binding to the same receptor, and if different signaling mechanisms can be induced, it will result in a very dynamic model for receptor activation, cellular signaling, and response.

When scrutinizing several hypotheses (Figure 6), it is impossible to include our findings within an existing pharmacological paradigm. The pharmacology does not suggest a mt:-receptor, nor a MT2, or a MT3 receptor and there is no evidence enough to suggest a new MT receptor subtype. What is at hand is an a2-adrenoceptor-melatonin interaction that implies a possibility for a two-site model.

We gratefully acknowledge Kristineberg Marine Research Station for supplying us with experimental fishes and laboratory facilities.

This work was supported by grants from: The Swedish Medical Research Council (04X-4498), Lions foundation, Ostergotlands lans landstings forskningsfond, The Royal Swedish Academy for Sciences and The Swedish Society for Medical Research.

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