Melanocortin-4 Receptor in Spotted Sea Bass, Lateolabrax maculatus: Cloning, Tissue Distribution, Physiology, and Pharmacology.

Kai-Qiang Zhang,Zhi-Shuai Hou,Yun Li,Xin Qi,Hai-Shen Wen,Wen-Juan Li,Ya-Xiong Tao

doi:10.3389/fendo.2019.00705

Kai-Qiang Zhang, Zhi-Shuai Hou + Show 5 more

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https://doi.org/10.3389/fendo.2019.00705

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Abstract

Melanocortin-4 receptor (MC4R) plays important roles in regulation of multiple physiological processes including energy homeostasis, reproduction, sexual function, and other functions in mammals. Recent studies suggested that teleost MC4Rs have different physiological functions and pharmacological characteristics when compared to mammalian MC4Rs. In this study, we investigated spotted sea bass (Lateolabrax maculatus) MC4R (LmMC4R) physiology and pharmacology. Spotted sea bass mc4r consisted of a 984 bp open reading frame encoding a protein of 327 amino acids. LmMC4R was homologous to those of several teleost MC4Rs and human MC4R (hMC4R). qRT-PCR and in situ hybridization revealed that mc4r transcripts were highly expressed in the brain, followed by pituitary and liver. Brain mc4r transcripts were down-regulated in long-term and short-term fasting challenges. LmMC4R was a functional receptor with lower maximal binding and higher basal activity than hMC4R. THIQ was not able to displace 125I-NDP-MSH but could affect intracellular cAMP accumulation, suggesting that it was an allosteric ligand for LmMC4R. In vitro studies with spotted sea bass brain cells indicated that mRNA levels of neuropeptide Y and Agouti-related peptide were down-regulated by α-MSH. In summary, we cloned spotted sea bass MC4R, and showed that it had different pharmacological properties compared to hMC4R, and potentially different functions.

Highlights

Melanocortin peptides are posttranslational products of proopiomelanocortin (POMC) that include α, β, and γ- melanocyte-stimulating hormones (α, β, and γ-MSH) and adrenocorticotropic hormone (ACTH) [reviewed in [1, 2]]
The total cDNA sequence of bass mc4r was 1,588 bp, containing an Open reading frame (ORF) of 984 bp that encoded a putative protein of 327 amino acids
Phylogenetic tree analysis between LmMC4R and Melanocortin-4 receptor (MC4R) in other vertebrates revealed that LmMC4R was localized in a clade of teleost MC4Rs and was evolutionarily closer to European sea bass MC4R (Figure 2B)

Summary

Introduction

Melanocortin peptides are posttranslational products of proopiomelanocortin (POMC) that include α-, β-, and γ- melanocyte-stimulating hormones (α-, β-, and γ-MSH) and adrenocorticotropic hormone (ACTH) [reviewed in [1, 2]]. Melanocortin peptides exert their effects by activating melanocortin receptors (MCRs). MC4R in Spotted Sea Bass α-MSH, ACTH and other POMC-derived peptides are endogenous agonists and Agouti-related peptide (AgRP) is endogenous antagonist of MC4R. Analogs of α-MSH and some small molecules have been identified as MC4R ligands. THIQ (N-[(3R)-1,2,3,4-tetrahydroisoquinolinium3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)- 2-[4-cyclohexyl-4-(1H1,2,4-triazol-1-ylmethyl)piperidin-1-yl]-2-oxoethylamine), is a small molecule agonist [6]

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