Biased signaling in drug discovery and precision medicine.

Receptors are crucial for converting chemical and environmental signals into cellular responses, making them prime targets in drug discovery, with about 70% of drugs targeting these receptors. Biased signaling, or functional selectivity, has revolutionized drug development by enabling precise modulation of receptor signaling pathways. This concept is more firmly established in G protein-coupled receptor and has now been applied to other receptor types, including ion channels, receptor tyrosine kinases, and nuclear receptors.

Are Melanocortin Receptors Present in Extant Protochordates?

Functional melanocortin receptor (MCR) genes have been identified in the genomes of early chordates, e.g., the cyclostomata.

SHU9119 and MBP10 are biased ligands at the human melanocortin-4 receptor.

The melanocortin-4 receptor (MC4R), a G protein-coupled receptor, is critically involved in regulating energy homeostasis as well as modulation of reproduction and sexual function. Two peptide antagonists (SHU9119 and MBP10) were derived from the endogenous agonist α-melanocyte stimulating hormone. But their pharmacology at human MC4R is not fully understood.

Differences in diacylglycerol acyltransferases expression patterns and regulation cause distinct hepatic triglyceride deposition in fish.

Triglyceride (TAG) deposition in the liver is associated with metabolic disorders. In lower vertebrate, the propensity to accumulate hepatic TAG varies widely among fish species. Diacylglycerol acyltransferases (DGAT1 and DGAT2) are major enzymes for TAG synthesis.

Divergent Pharmacology and Biased Signaling of the Four Melanocortin-4 Receptor Isoforms in Rainbow Trout ().

The melanocortin-4 receptor (MC4R) is essential for the modulation of energy balance and reproduction in both fish and mammals. Rainbow trout () has been extensively studied in various fields and provides a unique opportunity to investigate divergent physiological roles of paralogues. Herein we identified four trout (, , , and ) genes.

Modulation of Canine Melanocortin-3 and -4 Receptors by Melanocortin-2 Receptor Accessory Protein 1 and 2.

The neural melanocortin receptors (MCRs), melanocortin-3 and -4 receptors (MC3R and MC4R), have crucial roles in regulating energy homeostasis. The melanocortin-2 receptor accessory proteins (MRAPs, MRAP1 and MRAP2) have been shown to regulate neural MCRs in a species-specific manner. The potential effects of MRAP1 and MRAP2 on canine neural MCRs have not been investigated before.

Melanocortin-1 receptor mutations and pigmentation: Insights from large animals.

The melanocortin-1 receptor (MC1R) is a G protein-coupled receptor expressed in cutaneous and hair follicle melanocytes, and plays a central role in coat color determination in vertebrates. Numerous MC1R variants have been identified in diverse species. Some of these variants have been associated with specific hair and skin color phenotypes in humans as well as coat color in animals.

Mutations in rhodopsin, endothelin B receptor, and CC chemokine receptor 5 in large animals: Modeling human diseases.

G protein-coupled receptors (GPCRs) are the largest family of cell membrane receptors involved in modulating almost all physiological processes by transducing extracellular signals into the cytoplasm. Dysfunctions of GPCR-regulated signaling result in diverse human diseases, making GPCRs the most popular drug targets for human medicine. Large animals share higher similarities (in physiology and metabolism) with humans than rodents.

Demonstration of a Common DPhe to DNal(2') Peptide Ligand Antagonist Switch for Melanocortin-3 and Melanocortin-4 Receptors Identifies the Systematic Mischaracterization of the Pharmacological Properties of Melanocortin Peptides.

Melanocortin peptides containing a 3-(2-naphthyl)-d-alanine residue in position 7 (DNal(2')), reported as melanocortin-3 receptor (MC3R) subtype-specific agonists in two separate publications, were found to lack significant MC3R agonist activity. The cell lines used at the University of Arizona for pharmacological characterization of these peptides, consisting of HEK293 cells stably transfected with human melanocortin receptor subtypes MC1R, MC3R, MC4R, or MC5R, were then obtained and characterized by quantitative polymerase chain reaction (PCR). While the MC1R cell line correctly expressed only hMCR1, the three other cell lines were mischaracterized with regard to receptor subtype expression.

Regulation of Melanocortin-3 and -4 Receptors by Isoforms of Melanocortin-2 Receptor Accessory Protein 1 and 2.

The neural melanocortin receptors (MCRs), melanocortin-3 and -4 receptors (MC3R and MC4R), play essential non-redundant roles in the regulation of energy homeostasis. Interaction of neural MCRs and melanocortin-2 receptor accessory proteins (MRAPs, MRAP1 and MRAP2) is suggested to play pivotal roles in MC3R and MC4R signaling. In the present study, we identified two new human (h) splice variants, (465 bp open reading frame) and (381 bp open reading frame).

Topmouth culter melanocortin-3 receptor: regulation by two isoforms of melanocortin-2 receptor accessory protein 2.

Melanocortin-3 receptor (MC3R) is a regulator of energy homeostasis, and interaction of MC3R and melanocortin-2 receptor accessory protein 2 (MRAP2) plays a critical role in MC3R signaling of mammals. However, the physiological roles of MC3R in teleosts are not well understood. In this study, qRT-PCR was used to measure gene expression.

Oleic and palmitic acids induce hepatic angiopoietin-like 4 expression predominantly via PPAR- in .

Angiopoietin-like 4 (ANGPTL4) is a potent regulator of TAG metabolism, but knowledge of the mechanisms underlying ANGPTL4 transcription in response to fatty acids is still limited in teleost. In the current study, we explored the molecular characterisation of ANGPTL4 and regulatory mechanisms of ANGPTL4 in response to fatty acids in large yellow croaker (). Here, croaker contained a 1416 bp open reading frame encoding a protein of 471 amino acids with highly conserved 12-amino acid consensus motif.

Activation of Autophagy Relieves Linoleic Acid-Induced Inflammation in Large Yellow Croaker ().

High levels of soybean oil (SO) in fish diets enriched with linoleic acid (LA, 18:2n-6) could induce strong inflammation. However, the molecular mechanism underlying LA-induced inflammation in the liver of large yellow croaker () has not been elucidated. Based on previous research, autophagy has been considered a new pathway to relieve inflammation.

Effects of dietary curcumin on growth, antioxidant capacity, fatty acid composition and expression of lipid metabolism-related genes of large yellow croaker fed a high-fat diet.

A 10-week feeding trial was conducted to investigate the effect of dietary curcumin (CC) on growth antioxidant responses, fatty acid composition, and expression of lipid metabolism-related genes of large yellow croaker fed a high-fat diet (HFD). Four diets (lipid level at 18 %) were formulated with different levels of curcumin (0, 0·02, 0·04 and 0·06 %). The best growth performance was found in the 0·04 % curcumin group, with the body and hepatic lipid levels lower than the control group (0 % CC).

Regulation of Melanocortin-4 Receptor Pharmacology by Two Isoforms of Melanocortin Receptor Accessory Protein 2 in Topmouth Culter ().

Melanocortin-4 receptor (MC4R) plays important roles in regulation of multiple physiological processes, and interaction of MC4R and melanocortin receptor accessory protein 2 (MRAP2) is suggested to play pivotal role in energy balance of vertebrates. Topmouth culter () is an economically important freshwater fish in China. Herein we cloned culter , and .

Regulation of adiponectin on lipid metabolism in large yellow croaker (Larimichthys crocea).

Adiponectin (APN), an adipose tissue-derived hormone, plays a key role in regulating energy metabolism in mammals. However, its physiological roles in teleosts remain poorly understood. In the present study, the apn gene was cloned from large yellow croaker, which was mainly expressed in the adipose, muscle and liver.

High percentage of dietary palm oil suppressed growth and antioxidant capacity and induced the inflammation by activation of TLR-NF-κB signaling pathway in large yellow croaker (Larimichthys crocea).

A 70-day feeding trial was conducted to investigate the effects of dietary fish oil (FO) replaced by palm oil (PO) on growth, biochemical and antioxidant response as well as inflammatory response in the liver of large yellow croaker (initial weight 15.87 ± 0.14 g).

Influence of a Dietary Vegetable Oil Blend on Serum Lipid Profiles in Large Yellow Croaker ( Larimichthys crocea).

Serum lipid metabolic responses are associated with certain metabolic disorders induced by dietary habits in mammals. However, such associations have not been reported in fish. Lipidomic analyses were performed to investigate fish lipid metabolic responses to a dietary vegetable oil (VO) blend and to elucidate the mechanism of how the dietary VO blend affects serum lipid profiles.

Molecular cloning and characterization of farnesoid X receptor from large yellow croaker (Larimichthys crocea) and the effect of dietary CDCA on the expression of inflammatory genes in intestine and spleen.

In the present study, farnesoid X receptor (FXR) was cloned and characterized from liver of large yellow croaker (L crocea) and the effects of dietary chenodeoxycholic acid (CDCA), a nature ligand of FXR, on the inflammatory genes expression in the intestine and spleen of large yellow croaker were investigated. Multiple alignments showed that FXR of large yellow croaker contained highly conserved DNA-binding domain and ligand binding domain compared with other species. The subcellular localization analysis showed that FXR-GFP fusion protein could target to the nucleus in HEK 293t.

Omega-3 polyunsaturated fatty acids alleviate hepatic steatosis-induced inflammation through Sirt1-mediated nuclear translocation of NF-κB p65 subunit in hepatocytes of large yellow croaker (Larmichthys crocea).

Hepatic steatosis induced inflammation is becoming increasingly prevalent in farmed fish. This study was conducted to investigate the protective effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) against hepatic steatosis-induced inflammation and its potential molecular mechanisms in hepatocyte of large yellow croaker (Larmichthys crocea). We found that the hepatic steatosis-induced inflammation was relieved by ω-3 PUFAs, meanwhile, the Sirt1 activity and transcript expression was increased by ω-3 PUFAs.