Molecular determinants of ACTH receptor for ligand selectivity

Highlights

• ACTH receptor plays a key role in regulating adrenocortical function.

• In this review, we provide the latest understanding of ACTH receptor responsible for ligand function and selectivity.

• Developing ACTH receptor agonist or antagonist will be used for future human therapeutics.

Abstract

The adrenocorticotropic hormone (ACTH) receptor, known as the melanocortin-2 receptor (MC2R), plays a key role in regulating adrenocortical function. ACTH receptor is a subtype of the melanocortin receptor family which is a member of the G-protein coupled receptor (GPCR) superfamily. ACTH receptor has unique characteristics among MCRs. α-MSH, β-MSH, γ-MSH and ACTH are agonists for MCRs but only ACTH is the agonist for ACTH receptor. In addition, the melanocortin receptor accessory protein (MRAP) is required for ACTH receptor expression at cell surface and function. In this review, we summarized the information available on the relationship between ACTH and ACTH receptor and provide the latest understanding of the molecular basis of the ACTH receptor responsible for ligand selectivity and function.

Introduction

Adrenocorticotropic hormone (ACTH) is a polypeptide hormone produced and secreted by the anterior pituitary gland (Li et al., 1942). ACTH is classified as a member of the melanocortins (MCs) and stimulates secretion of glucocorticoid steroid hormones from adrenal cortex cells through ACTH receptor which is primarily found in the zona fasciculata of the adrenal cortex. The adrenocorticotropic hormone (ACTH) receptor, also known as the melanocortin-2 receptor (MC2R), is critical for ACTH-mediated adrenal glucocorticoid release (Yang and Harmon, 2017; Mountjoy et al., 1992; Chhajlani and Wikberg, 1992). ACTH binds to ACTH receptor and stimulates the adrenal glands to produce glucocorticoids which include cortisol and corticosterone. In addition, ACTH receptor is required for fetal and neonatal adrenal gland development (Roebuck et al., 1980; Lohse and First, 1981; McNulty et al., 1981; Chida et al., 2007). Deficiency of the ACTH receptor resulted in familial glucocorticoid deficiency (FGD) (Clark and Weber, 1998; Clark et al., 2005; Elias et al., 1999; Huebner et al., 1999; Chan et al., 2008). Patients with ACTH receptor deficiency have high levels of serum ACTH and low levels of cortisol due to an impaired adrenal responsiveness to ACTH (Habeb et al., 2013; Meimaridou et al., 2013a, 2013b; Abuduxikuer et al., 2019).

The melanocortin system consists of three components which are melanocortin peptides; melanocortin receptors; and two endogenous antagonists, agouti-signaling protein (ASIP) (agouti in rodents) and agouti-related protein (AGRP). Melanocortin peptides are composed of ACTH as well as α−, β−, and γ−melanocyte stimulating hormone (MSH) (Tatro and Reichlin, 1987; Tatro, 1996; Bicknell, 2002; Cooper et al., 1996; Clark et al., 1978; De Wied and Jolles, 1982; Catania et al., 1996; Gantz and Fong, 2003). To date, five melanocortin receptors have been cloned and each receptor has its own unique pattern of tissue expression and function (Gantz and Fong, 2003). ACTH binds to ACTH receptor, and, as with the other melanocortin peptides and receptors, stimulates adenylate cyclase, thereby elevating the second messenger, cellular cyclic AMP (cAMP). ACTH is the only known physiologic ligand for ACTH receptor, while α−, β−, and γ-MSH and ACTH are physiologic ligands for MC1R, MC3R, MC4R and MC5R (Schioth et al., 1996). The amino acid sequences of the melanocortins are shown in Fig. 1. ACTH is composed of 39 amino acid residues and shares the first 13 amino acids with MSH. They share the core sequence “His⁶-Phe⁷-Arg⁸-Trp⁹” which was identified as important residues for ligand binding and activities at human (h)MC1R, hACTH receptor, hMC3R, hMC4R and hMC5R (Holder et al., 2002a, 2002b, 2003a, 2003b; Todorovic et al., 2005; Haskell-Luevano et al., 1997; Shizume et al., 1954; Goldman and Hadley, 1970).

The ACTH receptor gene sequence was reported in 1992 by two research groups (Mountjoy et al., 1992; Chhajlani and Wikberg, 1992). ACTH receptor shares a nearly 40% homology with other melanocortin receptor subtypes, but it is unique among melanocortin receptor subtypes (Schioth et al., 1996). While ligand selectivity for melanocortin receptor family is usually achievable, it is often difficult to obtain selectivity among subtypes of the receptor family. There is no selective agonist or antagonist developed so far for ACTH receptor because detailed molecular basis of ACTH receptor for ligand selectivity is unclear. The design of ligands that provide receptor selectivity has emerged as a new paradigm for drug discovery of G protein-coupled receptors. For decades, the development of ligands in traditional GPCR-based drug discovery has focused on targeting the primary endogenous ligand (orthosteric) binding site of the receptor, guiding the development of the most classical orthosteric agonists, inverse agonists, and antagonists. However, many receptor subtypes in GPCR families often exhibit a highly conserved orthosteric binding site, such as a single ligand can interact with several receptor subtypes simultaneously, leading to the activation of the multiple receptor subtype, sometimes with opposing of their signaling profiles, resulting in side effects (Wootten et al., 2018; Seyedabadi et al., 2019). Although MCRs often share similar binding sites in their structures, it is often expected to design and synthesize ligands which can selectively bind to a specific receptor subtype and alter this specific receptor subtype function without affecting other receptor subtype. Designing and developing a selective agonist or antagonist for ACTH receptor remains a challenge task because the molecular basis of ACTH receptor responsible for ligand selectivity is not fully understood. ACTH is not only an agonist for ACTH receptor but it is also an agonist for other MCRs. All melanocortin ligands shared the same H⁶F⁷R⁸W⁹ motif, which is important for MCR binding and stimulation. Development of the ACTH receptor selective agonist or antagonist is challenging due to the conserved amino acid sequences of the MCRs and of their structural similarity in the seven-transmembrane GPCR fold. The limited structural variations of the endogenous melanocortin ligands further reduce options in the design of ACTH receptor ligands for achieving receptor subtype selectivity. If they are not selective, these peptides could be the source of severe undesirable effects due to the numerous specific roles of the five MCRs. Designing molecules that possess both melanocortin receptor selectivity and melanocortin receptor subtype selectivity from the melanotropin core sequence H⁶F⁷R⁸W⁹ has been difficult. Therefore, a better understanding of the molecular determinants of ACTH receptor responsible for ACTH selectivity is essential for our comprehensive understanding of ACTH receptor function and for the development of the selective ACTH receptor agonist or antagonist.