Review
Structure, function and regulation of the melanocortin receptors

https://doi.org/10.1016/j.ejphar.2010.12.020Get rights and content

Abstract

Melanocortin receptors belong to the seven-transmembrane (TM) domain proteins that are coupled to G-proteins and signaled through intracellular cyclic adenosine monophosphate. Many structural features conserved in other G-protein coupled receptors (GPCRs) are found in the melanocortin receptors. There are five melanocortin receptor subtypes and each of the melanocortin receptor subtypes has a different pattern of tissue expression and has its own profile regarding the relative potency of different melanocortin peptides. α-, β-, and γ-MSH and ACTH are known endogenous agonist ligands for the melanocortin receptors. Agouti and AgRP are the only known naturally occurring antagonists of the melanocortin receptors. We have examined the molecular basis of all five human melanocortin receptors for different ligand binding affinities and potencies using chimeric and mutated receptors. Our studies indicate that human melanocortin MC1 receptor, human melanocortin MC3 receptor, human melanocortin MC4 receptor and human melanocortin MC5 receptor utilize orthosteric sites for non selective agonists, α-MSH and NDP-α-MSH, high affinity binding and utilize allosteric sites for selective agonist or antagonist binding. Furthermore, our results indicate that molecular determinants of human melanocortin MC2 receptor for ACTH binding and signaling are different from that of other melanocortin receptors. Many studies also indicate that agonists can induce different conformation changes of melanocortin receptors, which then lead to the activation of different signaling pathways, even when the expression level of receptor and the strength of stimulus–response coupling are the same. This finding may provide new information for the design of drugs for targeting melanocortin receptors.

Introduction

The melanocortin system consists of 1) the melanocortin peptides α-, β-, and γ-melanocyte-stimulating hormone (α-, β-, γ-MSH) and adrenocorticotropic hormone (ACTH), 2) a family of five seven-transmembrane G protein-coupled melanocortin receptors, and 3) the endogenous melanocortin antagonists agouti and agouti-related protein (AgRP) (Cone et al., 1996, Gantz and Fong, 2003, Holder and Haskell-Luevano, 2004, Yang and Harmon, 2003). The melanocortins are involved in a diverse number of physiological functions, including pigmentation, steroidogenesis, energy homeostasis, exocrine secretion, sexual function, analgesia and inflammation. Melanocortin MC1 receptor is the melanocyte α-MSH receptor, expressed on cutaneous melanocytes, where it has a key role in determining skin and hair pigmentation. Melanocortin MC1 receptor is also expressed at leukocytes, where it may mediate the anti-inflammatory property. Melanocortin MC2 receptor is the adrenocortical ACTH receptor, expressed in the adrenal cortex zona reticularis and zona fasciculata, where it mediates the effects of ACTH on steroid secretion. Melanocortin MC3 receptor is identified in many areas of the central nervous system and peripheral tissues and involved in energy homeostasis. Melanocortin MC4 receptor is expressed predominantly in the central nervous system and regulates both food intake and sexual function. Melanocortin MC5 receptor is expressed in numerous human peripheral tissues and is mainly involved in exocrine function, particularly sebaceous gland secretion discovered by targeted deletion of that receptor (Adan et al., 1999, Cone, 1999, Cone, 2005, Gantz and Fong, 2003). The physiological significance of the melanocortin receptor family has promoted considerable research activity over the past decade (Adan et al., 1997, Adan and Vink, 2001, Chen et al., 2000a, Chen et al., 2000b, Chen et al., 2007a, Huszar et al., 1997, Hwa et al., 2001). The ultimate goal for the development of any new therapeutic agent for melanocortin receptors is to identify a drug that produces the desired effect with minimal side effects. To this end, the concept of directed signaling and functional selectivity has generated significant interest as a means to develop compounds that can selectively activate or block receptor-signaling pathways that lead only to the desired therapeutic effect. This is of particular importance for the melanocortin receptors as a potential target for the treatment of skin cancer, food intake, and exocrine disorders because many existing melanocortin receptor agonists for melanocortin receptors are not receptor subtype specific and have unwanted side effects. Several approaches have been undertaken to develop melanocortin receptor agonists and antagonists. In this review, current understanding of the molecular basis of human melanocortin receptors responsible for ligand binding and signaling will be discussed.

Section snippets

Structural features of the melanocortin receptors

Melanocortin receptors belong to the seven-transmembrane (TM) domain receptor proteins that are coupled to proteins G [G-protein-coupled receptors (GPCRs)] and signaled mainly through intracellular cyclic adenosine monophosphate. The cloning of the human melanocortin receptor genes has led to a tremendous progress in understanding the biological effects of the melanocortin peptides and the melanocortin receptors. So far, five human melanocortin receptor genes, including human melanocortin MC1

The orthosteric binding pocket in the melanocortin receptors

The orthosteric site is defined as the receptor area where the endogenous agonist binds. Melanocortin receptors share same endogenous ligands and therefore should have orthosteric binding sites for endogenous melanocortins. Sequence comparison of human melanocortin receptors shows high sequence homologies, ranging from 60% identity between human melanocortin MC4 receptor and melanocortin MC5 receptor, 45% identity between human melanocortin MC3 receptor and melanocortin MC1 receptor and between

An allosteric binding pocket in the melanocortin receptors

The allosteric site is defined as the receptor area that is distinct from the binding site of the endogenous ligands. Allosteric ligands alter receptor conformation through binding at sites distinct from the orthosteric ligand binding site. Melanocortin receptor family is a member of G-protein-coupled receptor families that share the same endogenous ligand. While ligand selectivity for melanocortin receptor family is usually achievable, it is often difficult to obtain selectivity among subtypes

Agonist-selective signaling of melanocortin receptors: Mechanism and implication

Melanocortin agonists bind to melanocortin receptors with high affinity and shift the receptor to its active conformation and induce a physiological effect. Recent studies indicate that agonists possess different efficacies on different signaling pathways of particular melanocortin receptors (1, 2). A new theory may accommodate these phenomena that melanocortin agonist can induce different conformation changes of one particular melanocortin receptor, which then lead to the activation of

Melanocortin receptor modeling using computational methods

To obtain accurate information on the three-dimensional surrounding the binding pocket of melanocortin receptors is a big challenge and the knowledge of the melanocortin receptor's three-dimensional structure is critical to understanding how melanocortin receptors carry out their functions. For GPCR, the three dimensional structure of a receptor is usually obtained from X-ray crystallography studies, but for most GPCRs crystallization is still an unresolved problem. An alternative approach to

Conclusion

Melanocortin receptor family is of the most important class of GPCR in the genome because of its tremendous molecular diversity and potential targets for therapeutic application. The majority of current ligands affect melanocortin receptor activity by binding to orthosteric site as the endogenous cognate ligand for the receptor. Over the past one decade, novel opportunities for drug discovery have risen from a greater understanding of the complexity of melanocortin receptor signaling. A

References (44)

  • D. Huszar et al.

    Targeted disruption of the melanocortin-4 receptor results in obesity in mice

    Cell

    (1997)
  • J. Oosterom et al.

    Common requirements for melanocortin-4 receptor selectivity of structurally unrelated melanocortin agonist and endogenous antagonist, Agouti protein

    J. Biol. Chem.

    (2001)
  • Y. Yang et al.

    Molecular basis for the interaction of [Nle4, D-Phe7]melanocyte stimulating hormone with the human melanocortin-1 receptor

    J. Biol. Chem.

    (1997)
  • Y.K. Yang et al.

    Contribution of melanocortin receptor exoloops to Agouti-related protein binding

    J. Biol. Chem.

    (1999)
  • Y. Yang et al.

    Molecular determinants of human melanocortin-4 receptor responsible for antagonist SHU9119 selective activity

    J. Biol. Chem.

    (2002)
  • R.A. Adan et al.

    Molecular pharmacology of neural melanocortin receptors

    Recept. Channels

    (1997)
  • B. Chai et al.

    Melanocortin-3 receptor activates MAP kinase via PI3 kinase

    Regul. Pept.

    (2006)
  • A.S. Chen et al.

    Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass

    Nat. Genet.

    (2000)
  • A.S. Chen et al.

    Role of the melanocortin-4 receptor in metabolic rate and food intake in mice

    Transgenic Res.

    (2000)
  • M. Chen et al.

    Molecular characterization of human melanocortin-3 receptor ligand–receptor interaction

    Biochemistry

    (2006)
  • C. Chen et al.

    Discovery of 1-[2-[(1 S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-4-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)-propionyl]piperazine as an orally active antagonist of the melanocortin-4 receptor for the potential treatment of cachexia

    J. Med. Chem.

    (2007)
  • M. Chen et al.

    Molecular identification of the human melanocortin-2 receptor responsible for ligand binding and signaling

    Biochemistry

    (2007)
  • Cited by (0)

    View full text