Evolution of Structural and Functional Diversity of Spexin in Mammalian and Non-mammalian Vertebrate Species

Abstract

Spexin (SPX) is a novel neuropeptide, which was first identified in the human genome using bioinformatics. Since then, orthologs of human SPX have been identified in mammalian and non-mammalian vertebrates. The mature sequence of SPX, NWTPQAMLYLKGAQ, is evolutionally conserved across vertebrate species, with some variations in teleost species where Ala at position 13 is substituted by Thr. In mammals, the gene structure of SPX comprises six exons and five introns, however, variation exists within non-mammalian species, goldfish and zebrafish having five exons while grouper has six exons. Phylogenetic and synteny analysis, reveal that SPX is grouped together with two neuropeptides, kisspeptin (KISS) and galanin (GAL) as a family of peptides with a common evolutionary ancestor. A paralog of SPX, termed SPX2 has been identified in non-mammalians but not in the mammalian genome. Ligand-receptor interaction study also shows that SPX acts as a ligand for GAL receptor 2 (2a and 2b in non-mammalian vertebrates) and 3. SPX acts as a neuromodulator with multiple central and peripheral physiological roles in the regulation of insulin release, fat metabolism, feeding behavior, and reproduction. Collectively, this review provides a comprehensive overview of the evolutionary diversity as well as molecular and physiological roles of SPX in mammalian and non-mammalian vertebrate species.

Spexin and a Novel Cichlid-Specific Spexin Paralog Both Inhibit FSH and LH Through a Specific Galanin Receptor (Galr2b) in Tilapia

“…Spexin has wide tissue distribution patterns in tetrapods and fish, suggesting that spexin has pleiotropic biological consequences in feeding behavior, metabolism, nociception, cardiovascular function, muscle motility, stress, depression, and anxiety (3). The localization of spexins at the cellular level inform these functions.…”

“…The fish were bled from the caudal blood vessels into heparinized syringes at 2, 4, 8, and 24 h after injection. Blood was centrifuged (3,200 rpm for 30 min at 4 • C) to obtain plasma samples, which were stored at −20 • C until assayed. This time course is according to standard protocols used previously to test the effect of various hypothalamic neuropeptides on circulating levels of LH and FSH in tilapia (35,36).…”

“…The mature spexin peptide was found to be identical in all tetrapods and elephant shark, and differs in only one amino acid (A 13 T) in piscine species. A paralog of spexin, termed Spx2, was later identified in non-mammalian species (3). In mammals, Spx was found to participate in inducing stomach contraction (1), inhibiting adrenocortical cell proliferation (4), postnatal hypoxia response (5), cardiovascular and renal modulation (6), nociceptive response (7), fatty acid absorption and weight regulation (8), and diabetes (9).…”

Peripheral Spexin Inhibited Food Intake in Mice

“…In human, Spexin encoded a prepropeptide of 116 amino acids, which generated a mature peptide undergoing process of posttranslational modifications [ 2 ]. The sequence of mature spexin containing 14 amino acids (NWTPQAMLYLKGAQ) was conserved across vertebrate species [ 3 ]. The gene structure analysis indicated that spexin was closely related to galanin and kisspeptin [ 4 ].…”

“…Spexin gene or protein had a wide distribution in the central nervous system (CNS) and peripheral tissues in several species, including human, rodents, chicken, anole lizard, and several fish species [ 3 ]. In rat, the spexin protein was observed in stomach fundus, epithelium of small intestine, submucosal layer of esophagus, and hepatocytes [ 5 ].…”