Structure and Expression of GPR54

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GPR54 receptor is a member of the rhodopsin family of G protein-coupled receptor superfamily. It was first cloned in 1999 as an orphan receptor in brain of rats.14 Based on the high-sequence conservation of G protein-coupled receptor transmembrane regions, Canadian researchers used the degenerate PCR strategy to discover this new receptor.14 The rat GPR54 contains an open reading frame of 1191 bp encoding for a protein of 396 amino acids and has 30-40% of homology to galanin receptors. Using in situ hybridization of rat brain sections, the distribution of GPR54 mRNA was found to be discretely localized in many areas.14 However, the highest levels of expression in rat brain were seen in hypothalamic and amygdaloid nuclei.14 A BLAST search with the rat GPR54 sequence revealed high identity with a human 3.5 Mb contig located in chromosome 19p13.3.14

The human GPR54 gene has five exons and four introns in a length of approximately 3.5 kb. It encodes a seven-transmembrane receptor with 398 amino acids and has also a weak homology with the galanin receptors, although neither galanin nor galanin- like peptide bind to GPR54 (Fig. 1).14-16 The human GPR54 receptor, also named AXOR12 and hOT7T175, is widely expressed in the brain, particularly in the hypothalamus, midbrain, pons, medulla, hippocampus, and amygdala and also in the pituitary, pancreas, placenta, and spinal cord.14-16 Lower level expression was found in the heart, muscle, kidney, liver, intestine, thymus, lung, and testis.14-16

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Fig. 1. Schematic representation of the G protein-coupled receptor 54 (GPR54). It is a seven-transmembrane receptor, with three extracellular (e1, e2, and e3), and three intracellular (i1, i2, and i3) loops together with one extracellular amino-terminal tail (-NH2) and one intracellular carboxy-terminal tail (-COOH). The GPR54 inactivating mutations described so far in patients with normosmic hypogonadotropic hypogonadism are represented by black dots. The unique nonconstitutively activating mutation is indicated in a red dot.

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Fig. 1. Schematic representation of the G protein-coupled receptor 54 (GPR54). It is a seven-transmembrane receptor, with three extracellular (e1, e2, and e3), and three intracellular (i1, i2, and i3) loops together with one extracellular amino-terminal tail (-NH2) and one intracellular carboxy-terminal tail (-COOH). The GPR54 inactivating mutations described so far in patients with normosmic hypogonadotropic hypogonadism are represented by black dots. The unique nonconstitutively activating mutation is indicated in a red dot.

Notably, the human GPR54 gene contains a GC-rich sequence. This sequence feature could be a complicate factor for gene amplification in human studies, requiring generally special PCR conditions for human DNA analysis.7 Alignment of the predicted amino acid sequences of GPR54 from mammalian and nonmammalian species reveals that the percentage of homology between GPR54 from primates and rodent sequences is greater than 80%.17 This high degree of sequence conservation for the receptor indicates that GPR54 is well conserved during evolution.17

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