Melatonin receptor genes in vertebrates

Abstract

Melatonin receptors are members of the G protein-coupled receptor (GPCR) family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A) and MT2 (or Mel1b or MTNR1B) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C), has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor.

Figure 1

Seven-transmembrane structure of typical melatonin receptors from most vertebrate species (panel A), and deviations of cat MTNR1A (panel B) and GPR50 (panel C). Sequences were examined by a transmembrane protein topology prediction method based on a hidden Markov model (TMHMM) [55] for the presence of seven trans-membrane domains.

Figure 1

Seven-transmembrane structure of typical melatonin receptors from most vertebrate species (panel A), and deviations of cat MTNR1A (panel B) and GPR50 (panel C). Sequences were examined by a transmembrane protein topology prediction method based on a hidden Markov model (TMHMM) [55] for the presence of seven trans-membrane domains.

Figure 2

Sequence alignment of amino acids (AA) encoded by vertebrate MTNR1A; ‘.’ indicates the same AA, ‘-’ indicates an AA deletion. Two insertions of cat AA sequence are boxed.

Figure 3

Neighbor-Joining (N-J) tree of melatonin receptors (panel A) constructed with protein Poisson distances; N-J tree of melatonin receptors and GPR50 (panel B).