scholarly journals MOLECULAR EVOLUTION OF GPCRS: Melanocortin/melanocortin receptors

2014 ◽  
Vol 52 (3) ◽  
pp. T29-T42 ◽  
Author(s):  
Robert M Dores ◽  
Richard L Londraville ◽  
Jeremy Prokop ◽  
Perry Davis ◽  
Nathan Dewey ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Focal Point ◽  
Cartilaginous Fish ◽  
G Protein Coupled Receptors ◽  
Melanocortin Receptors ◽  
Accessory Proteins ◽  
Melanocortin 1 Receptor ◽  
Ligand Selectivity ◽  
G Protein Coupled ◽  
Receptor Accessory Protein

The melanocortin receptors (MCRs) are a family of G protein-coupled receptors that are activated by melanocortin ligands derived from the proprotein, proopiomelanocortin (POMC). During the radiation of the gnathostomes, the five receptors have become functionally segregated (i.e. melanocortin 1 receptor (MC1R), pigmentation regulation; MC2R, glucocorticoid synthesis; MC3R and MC4R, energy homeostasis; and MC5R, exocrine gland physiology). A focus of this review is the role that ligand selectivity plays in the hypothalamus/pituitary/adrenal–interrenal (HPA–I) axis of teleosts and tetrapods as a result of the exclusive ligand selectivity of MC2R for the ligand ACTH. A second focal point of this review is the roles that the accessory proteins melanocortin 2 receptor accessory protein 1 (MRAP1) and MRAP2 are playing in, respectively, the HPA–I axis (MC2R) and the regulation of energy homeostasis by neurons in the hypothalamus (MC4R) of teleosts and tetrapods. In addition, observations are presented on trends in the ligand selectivity parameters of cartilaginous fish, teleost, and tetrapod MC1R, MC3R, MC4R, and MC5R paralogs, and the modeling of the HFRW motif of ACTH(1–24) when compared with α-MSH. The radiation of the MCRs during the evolution of the gnathostomes provides examples of how the physiology of endocrine and neuronal circuits can be shaped by ligand selectivity, the intersession of reverse agonists (agouti-related peptides (AGRPs)), and interactions with accessory proteins (MRAPs).

scholarly journals Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor

2021 ◽  
Author(s):  
Shanshan Ma ◽  
Yan Chen ◽  
Antao Dai ◽  
Wanchao Yin ◽  
Jia Guo ◽  
...  
Keyword(s):  
G Protein ◽  
Energy Homeostasis ◽  
Skin Pigmentation ◽  
Binding Pocket ◽  
Melanocortin Receptors ◽  
Melanocortin 1 Receptor ◽  
Structural Mechanism ◽  
Stimulatory G Protein ◽  
G Protein Coupled

Melanocortins are peptide hormones critical for stress response, energy homeostasis, inflammation, and skin pigmentation. Their functions are mediated by five G protein-coupled receptors (MC1R to MC5R), predominately through the stimulatory G protein (Gs). MC1R, the founding member of melanocortin receptors, is mainly expressed in melanocytes and is involved in melanogenesis. Dysfunction of MC1R is associated with the development of melanoma and skin cancer. Here we present three cryo-electron microscopy structures of the MC1R-Gs complexes bound to endogenous hormone α-MSH, a marketed drug afamelanotide, and a synthetic agonist SHU9119. These structures reveal the orthosteric binding pocket for the conserved HFRW motif among melanocortins and the crucial role of calcium ion in ligand binding. They also demonstrate the basis of differential activities among different ligands. In addition, unexpected interactions between MC1R and the Gβ subunit were discovered from these structures. Together, our results provide a conserved mechanism of calcium-mediated ligand recognition, specific mode of G protein coupling, and a universal activation pathway of melanocortin receptors.

scholarly journals The human non-visual opsin OPN3 regulates pigmentation of epidermal melanocytes through interaction with MC1R

2019 ◽  
Author(s):  
Rana N. Ozdeslik ◽  
Lauren E. Olinski ◽  
Melissa M. Trieu ◽  
Daniel D. Oprian ◽  
Elena Oancea
Keyword(s):  
Light Sensitivity ◽  
G Protein Coupled Receptors ◽  
Negative Regulator ◽  
Melanin Production ◽  
Melanocortin 1 Receptor ◽  
Skin Cells ◽  
Skin Physiology ◽  
Human Melanocytes ◽  
G Protein Coupled ◽  
The Brain

AbstractOpsins form a family of light-activated, retinal-dependent G-protein coupled receptors (GPCRs) that serve a multitude of visual and non-visual functions. Opsin3 (OPN3 or encephalopsin), initially identified in the brain, remains one of the few members of the mammalian opsin family with unknown function and ambiguous light-absorption properties. We recently discovered that OPN3 is highly expressed in human epidermal melanocytes—the skin cells that produce melanin. The melanin pigment is a critical defense against ultraviolet radiation and its production is mediated by the Gαs-coupled melanocortin-1 receptor (MC1R). The physiological function and light-sensitivity of OPN3 in melanocytes is yet to be determined. Here we show that in human epidermal melanocytes OPN3 acts as a negative regulator of melanin production by interacting with MC1R and modulating its cAMP signaling. OPN3 negatively regulates the cAMP response evoked by MC1R via activation of the Gαi subunit of G-proteins, thus decreasing cellular melanin levels. In addition to their functional relationship, OPN3 and MC1R colocalize at both the plasma membrane and in intracellular structures and form a physical complex. Remarkably, OPN3 can bind retinal, but does not mediate light-induced signaling in melanocytes. Our results identify a novel function for OPN3 in the regulation of the melanogenic pathway in epidermal melanocytes. Our results reveal a light-independent function for the poorly characterized OPN3 and a novel pathway that greatly expands our understanding of melanocyte and skin physiology.SignificanceOur data reveals a novel function for the non-visual opsin OPN3 in regulating the pigmentation of human melanocytes by interacting with and modulating the activity of MC1R.

scholarly journals Association of a missense mutation of the <i>MC4R</i> gene with growth traits in cattle (Brief report) (Assoziation einer Mutation im MC41 Gen mit Wachstumsmerkmalen beim Rind)

2006 ◽  
Vol 49 (5) ◽  
pp. 515-516
Author(s):  
C. L. Zhang ◽  
H. Chen ◽  
Y. H. Wang ◽  
X. Y. Lan ◽  
L. Zhang ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Energy Homeostasis ◽  
Growth Traits ◽  
G Protein Coupled Receptors ◽  
Ingestive Behavior ◽  
Coding Region ◽  
Mc4r Gene ◽  
Melanocortin 4 Receptor ◽  
G Protein Coupled ◽  
Human And Mouse

Abstract. Melanocortin-4 receptor (MC4R) is one of five G-protein-coupled receptors binding melanocortins that is implicated in the control of ingestive behavior and energy homeostasis. Mutations have been described in the human and mouse MC4R genes which are associated with obesity (YEO et al., 1998; HUSZAR et al., 1997). Moreover, a mutation in porcine MC4R is associated with economically important traits in the pig (KIM et al., 2000). The SNPs reported in bovine MC4R coding region were specific to breeds (VALLE et al., 2004; THUE et al., 2001; HAEGEMAN et al., 2001). In the present experiment over 95% of the coding region of MC4R were screened to detect the SNPs in the predominant cattle breeds of China. Association of a missense mutation of MC4R gene with growth traits was analyzed.

Extracellular loops and ligand binding to a subfamily of Family A G-protein-coupled receptors

2007 ◽  
Vol 35 (4) ◽  
pp. 717-720 ◽  
Author(s):  
M. Wheatley ◽  
J. Simms ◽  
S.R. Hawtin ◽  
V.J. Wesley ◽  
D. Wootten ◽  
...  
Keyword(s):  
Ligand Binding ◽  
G Protein ◽  
Tertiary Structure ◽  
Large Family ◽  
Peptide Hormone ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Ligand Selectivity ◽  
Extracellular Loops ◽  
G Protein Coupled

GPCRs (G-protein-coupled receptors) are a large family of structurally related proteins which mediate their effects by coupling to G-proteins. The V1aR (V1a vasopressin receptor) is a member of a family of related GPCRs that are activated by vasopressin {AVP ([Arg8]vasopressin)}, OT (oxytocin) and related peptides. These receptors are members of a subfamily of Family A GPCRs called the neurohypophysial peptide hormone receptor family. GPCRs exhibit a conserved tertiary structure comprising a bundle of seven TM (transmembrane) helices linked by alternating ECLs (extracellular loops) and ICLs (intracellular loops). The cluster of TM helices is functionally important for ligand binding, and, furthermore, activation of GPCRs involves movement of these TM helices. Consequently, it might be assumed that the extracellular face of GPCRs is composed of peptide linkers that merely connect important TM helices. However, using a systematic mutagenesis approach and focusing on the N-terminus and the second ECL of the V1aR, we have established that these extracellular domains fulfil a range of important roles with respect to GPCR signalling, including agonist binding, ligand selectivity and receptor activation.

scholarly journals Update on GPCR-based targets for the development of novel antidepressants

2021 ◽  
Author(s):  
Ioannis Mantas ◽  
Marcus Saarinen ◽  
Zhi-Qing David Xu ◽  
Per Svenningsson
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
G Protein ◽  
Therapeutic Potential ◽  
G Protein Coupled Receptors ◽  
Major Depressive ◽  
Ligand Selectivity ◽  
Direct Targeting ◽  
Atypical Antidepressants ◽  
G Protein Coupled

AbstractTraditional antidepressants largely interfere with monoaminergic transport or degradation systems, taking several weeks to have their therapeutic actions. Moreover, a large proportion of depressed patients are resistant to these therapies. Several atypical antidepressants have been developed which interact with G protein coupled receptors (GPCRs) instead, as direct targeting of receptors may achieve more efficacious and faster antidepressant actions. The focus of this review is to provide an update on how distinct GPCRs mediate antidepressant actions and discuss recent insights into how GPCRs regulate the pathophysiology of Major Depressive Disorder (MDD). We also discuss the therapeutic potential of novel GPCR targets, which are appealing due to their ligand selectivity, expression pattern, or pharmacological profiles. Finally, we highlight recent advances in understanding GPCR pharmacology and structure, and how they may provide new avenues for drug development.

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