Vertebrates originally possess four functional subtypes of G protein-coupled melatonin receptor

Abstract

Melatonin receptors (MTNRs) belonging to the G protein-coupled receptor family are considered to consist of three subtypes in vertebrates: MTNR1a, MTNR1b and MTNR1c. Additionally, MTNR1a-like genes have been identified in teleostean species as a fish-specific subtype of MTNR1a. However, similar molecules to this MTNR1a-like gene can be found in some reptiles upon searching the DNA database. We hypothesized that a vertebrate can essentially have four functional subtypes of MTNR as ohnologs. Thus, in the present study we examined the molecular phylogeny, expression patterns and pharmacological profile(s) using the teleost medaka ( Oryzias latipes ). The four conserved subtypes of MTNR (MTNR1a, MTNR1b, MTNR1c and MTNR1a-like) in vertebrates were classified based on synteny and phylogenetic analysis. The fourth MTNR, termed MTNR1a-like, could be classified as MTNR1d. It was observed by using RT-qPCR that expression patterns differed amongst these subtypes. Moreover, mtnr1a , mtnr1c and mtnr1a-like / mtnr1d expression was elevated during short days compared to long days in diencephalons. All the subtypes were activated by melatonin and transduced signals into the Gi pathway, to perform a cAMP-responsive reporter gene assay. It was shown that MTNR originally consisted of four subtypes: MTNR1a, MTNR1b, MTNR1c and MTNR1d. These subtypes were functional, at least in fish, although some organisms, including mammals, have lost one or two subtypes.

New Insights Into the Evolutionary History of Melatonin Receptors in Vertebrates, With Particular Focus on Teleosts

“…Our results suggest that the four melatonin receptors mediate distinct central and peripheral actions of melatonin in medaka. As in a previous study in medaka, high expression of mtnr1a, mtnr1b, and mtnr1d paralogs occurred in the brain and eye, which concurs with the role of the brain in the integration of photoperiodic signal (11,14,97,98).…”

“…The disruption of melatonin signaling is associated with the acquisition of an unihemispheric sleeping lifestyle and the development of long-term vigilance (85). The apparent absence of mtnr1d in all mammalian genomes examined, even in metatherians and in monotremes, confirms the loss of mtnr1d in the mammalian lineage (11,12). So far, mtnr1d had only been found missing in birds and mammals (11,12).…”

“…Medaka only retained one of the 3R paralogs of each vertebrate mtnr gene. The four receptors are able to respond specifically to melatonin by eliciting the inhibition of cAMP via inhibitory G protein in transfected Hepa-E1 cells (11). Studies have shown that seasonal and daily photoperiod changes affect physiological functions and behavior in medaka.…”

“…Recently, it was shown that the additional teleost mtnr1a-like gene is also present in some tetrapods (mtnr1a2 or mtnr1a1. 4) and consequently constitutes a fourth MTNR subtype named MTNR1D or MTNR1A-like (7)(8)(9)(10)(11)(12). The four MTNR monophyletic groups presumably derive from the two rounds of vertebrate tetraploidization early in vertebrate evolution (1R and 2R) (10)(11)(12).…”

“…4) and consequently constitutes a fourth MTNR subtype named MTNR1D or MTNR1A-like (7)(8)(9)(10)(11)(12). The four MTNR monophyletic groups presumably derive from the two rounds of vertebrate tetraploidization early in vertebrate evolution (1R and 2R) (10)(11)(12). Sakai et al reported that teleost species possess the four vertebrate MTNR subtypes but did not observe any further expansion of the mtnr gene repertoire in teleosts (11).…”