Heteromeric MT1/MT2 Melatonin Receptors Modulate Photoreceptor Function
Melatonin stimulates a heteromeric G protein coupled receptor to modulate the eye's response to light flashes at night. Flash Response In the retina, melatonin increases photoreceptor sensitivity to light at night, but not in mice deficient in the melatonin receptor MT1. Baba et al. found that two melatonin receptors, the G protein (heterotrimeric guanine nucleotide binding protein) coupled receptors (GPCRs) MT1 and MT2, were both present in the photoreceptor cells of mice, and, when coexpressed in cultured cells, these receptors formed homomeric and heteromeric complexes. Mice deficient in MT2 or expressing a mutant form of MT2 failed to respond to melatonin, suggesting that MT1 and MT2 may function as a heteromeric complex to mediate this response. By testing the response in the presence of various pharmacological agents, melatonin mediated its effect on photoreceptor responses in vivo through the inositol trisphosphate to protein kinase C pathway. Thus, this study delineates a pathway by which melatonin affects vision and provides in vivo evidence for functional GPCR heteromers. The formation of G protein (heterotrimeric guanine nucleotide binding protein) coupled receptor (GPCR) heteromers enables signaling diversification and holds great promise for improved drug selectivity. Most studies of these oligomerization events have been conducted in heterologous expression systems, and in vivo validation is lacking in most cases, thus questioning the physiological significance of GPCR heteromerization. The melatonin receptors MT1 and MT2 exist as homomers and heteromers when expressed in cultured cells. We showed that melatonin MT1/MT2 heteromers mediated the effect of melatonin on the light sensitivity of rod photoreceptors in mice. This effect of melatonin involved activation of the heteromer specific phospholipase C and protein kinase C (PLC/PKC) pathway and was abolished in MT1 or MT2 mice, as well as in mice overexpressing a nonfunctional MT2 mutant that interfered with the formation of functional MT1/MT2 heteromers in photoreceptor cells. Not only does this study establish an essential role of melatonin receptor heteromers in retinal function, it also provides in vivo support for the physiological importance of GPCR heteromerization. Thus, the MT1/MT2 heteromer complex may provide a specific pharmacological target to improve photoreceptor function.
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