Melatonin membrane receptors in peripheral tissues: distribution and functions

Abstract

Many of melatonin's actions are mediated through interaction with the G-protein coupled membrane bound melatonin receptors type 1 and type 2 (MT1 and MT2, respectively) or, indirectly with nuclear orphan receptors from the RORα/RZR family. Melatonin also binds to the quinone reductase II enzyme, previously defined the MT3 receptor. Melatonin receptors are widely distributed in the body; herein we summarize their expression and actions in non-neural tissues. Several controversies still exist regarding, for example, whether melatonin binds the RORα/RZR family. Studies of the peripheral distribution of melatonin receptors are important since they are attractive targets for immunomodulation, regulation of endocrine, reproductive and cardiovascular functions, modulation of skin pigmentation, hair growth, cancerogenesis, and aging. Melatonin receptor agonists and antagonists have an exciting future since they could define multiple mechanisms by which melatonin modulates the complexity of such a wide variety of physiological and pathological processes.

Fig. 1

The biosynthetic pathway of melatonin. Melatonin is synthesized from tryptophan in a multistep process. The final two synthetic steps mediated by AANAT and HIOMT are considered to be rate limiting. TRPH: tryptophan hydroxylase, AAD: aromatic amino acid decarboxylase, AANAT: arylalkylamine N-acetyltransferase, HIOMT: hydroxyindole-O-methyl transferase.

Fig. 2

Signaling schematic of melatonin receptor subtypes. Melatonin exerts many of its biological actions through MT1 or MT2 membrane receptors (G protein-coupled) or, according to some authors, via nuclear receptors (RORa/RZR1). Signaling pathways known to be activated by melatonin receptors are shown. Quinone reductase II (“MT3” receptors) have been demonstrated only in hamster and rabbit.