Abstract
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of food intake and energy expenditure. Melanocortin-2 receptor accessory protein 2 (MRAP2) modulates trafficking, ligand binding, and signaling of MC4R. The Northern snakehead (Channa argus) is an economically important freshwater fish native to East Asia. To explore potential interaction between snakehead MC4R and MRAP2, herein we cloned snakehead mc4r and mrap2. The snakehead mc4r consisted of a 984 bp open reading frame encoding a protein of 327 amino acids, while snakehead mrap2 contained a 693 bp open reading frame encoding a protein of 230 amino acids. Synteny analysis indicated that mc4r was highly conserved with similar gene arrangement, while mrap2 contained two isoforms in teleost with different gene orders. Snakehead mc4r was primarily expressed in the brain, whereas mrap2 was expressed in the brain and intestine. Snakehead mc4r and mrap2 expression was modulated by fasting and refeeding. Further pharmacological experiments showed that the cloned snakehead MC4R was functional, capable of binding to peptide agonists and increasing intracellular cAMP production in a dose-dependent manner. Snakehead MC4R exhibited high constitutive activity. MRAP2 significantly decreased basal and agonist-stimulated cAMP signaling. These findings suggest that snakehead MC4R might be involved in energy balance regulation by interacting with MRAP2. Further studies are needed to elucidate MC4R in regulating diverse physiological processes in snakehead.
Highlights
Introduction iationsThe melanocortin-4 receptor (MC4R), a Family A G protein-coupled receptor (GPCR), plays a central role in energy homeostasis regulation in mammals [1,2]
The results showed that caMRAP2 dose-dependently decreased the basal cAMP levels (Figure 11A)
Sequence comparison showed that caMC4R shared more than 80% amino acid identity with other teleost MC4Rs, whereas caMRAP2 shared lower identity (37.5–77.5%) with other teleost Melanocortin-2 receptor accessory protein 2 (MRAP2), suggesting MC4R was more conserved than MRAP2 in teleosts
Summary
The melanocortin-4 receptor (MC4R), a Family A G protein-coupled receptor (GPCR), plays a central role in energy homeostasis regulation in mammals [1,2]. It consists of the hallmark seven transmembrane domains (TMDs) connected by alternating extracellular and intracellular loops, with an extracellular N-terminus and intracellular C-terminus [3]. In 1997, it was discovered that modulation of MC4R activation or genetic inactivation exerts a profound influence on food intake and energy expenditure [5,6,7]. Subsequent studies found that mutations in MC4R and common genetic variation near MC4R lead to a dominant form of obesity and Licensee MDPI, Basel, Switzerland
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