Mechanism of Action: GHS-R1a

GHS-R1a Structure and Function

The Growth Hormone Secretagogue Receptor type 1a (GHS-R1a), or ghrelin receptor, is a Class A G protein-coupled receptor (GPCR). It consists of seven transmembrane domains and is primarily known for mediating the effects of ghrelin, including the stimulation of growth hormone secretion, appetite regulation, and energy homeostasis [1, 2]. Its expression is highest in the anterior pituitary and hypothalamus but is also found in other brain regions and peripheral tissues, indicating diverse physiological roles [1]. Recent advances in structural biology have provided insights into its ligand-binding pockets and conformational changes upon activation, aiding structure-based drug design [1].

The Ghrelin System: Ligands and Activation

The GHS-R1a signaling system involves several key players:

• Ghrelin: The primary endogenous ligand for GHS-R1a. It is unique among peptide hormones as it requires acylation, typically with an n-octanoyl group on its third serine residue (Ser3), for full biological activity and binding to GHS-R1a [2]. Unacylated ghrelin (UAG) does not activate GHS-R1a but may have other biological roles.
• GOAT (Ghrelin O-acyltransferase): This enzyme, a member of the membrane-bound O-acyltransferase (MBOAT) family, is responsible for attaching the fatty acid chain (usually octanoate) to Ser3 of ghrelin, converting inactive proghrelin into active, acylated ghrelin [2]. GOAT's unique substrate specificity makes it an attractive therapeutic target for modulating active ghrelin levels.
• LEAP2 (Liver-expressed antimicrobial peptide 2): Discovered more recently, LEAP2 acts as an endogenous antagonist or inverse agonist at the GHS-R1a receptor. It competes with ghrelin for binding and can inhibit both ghrelin-induced and constitutive receptor activity [1, 2]. LEAP2 levels are regulated by nutritional status, increasing after feeding and in obesity, potentially contributing to ghrelin resistance [2]. The interplay between ghrelin, GOAT, and LEAP2 creates a complex regulatory network for GHS-R1a signaling.

Signaling Pathways and Constitutive Activity

GHS-R1a exhibits an unusually high level of constitutive activity, estimated at around 50% of its maximal response even without ghrelin binding [1]. This baseline activity contributes significantly to its physiological effects and makes inverse agonists (which suppress this activity) a viable therapeutic strategy.

Upon activation by ghrelin or synthetic agonists, GHS-R1a couples to various intracellular signaling pathways:

• Gαq/11 Pathway: Considered the canonical pathway, leading to activation of phospholipase C (PLC), production of inositol trisphosphate (IP3) and diacylglycerol (DAG), and subsequent increase in intracellular calcium levels and protein kinase C (PKC) activation. This pathway is crucial for GH secretion [1, 2].
• Other G Proteins: GHS-R1a can also couple to Gαi/o, Gαs, and Gα12/13 pathways, depending on the cellular context and ligand, leading to modulation of adenylyl cyclase activity (cAMP levels) or Rho activation [1, 2].
• β-Arrestin Pathway: Like many GPCRs, GHS-R1a recruits β-arrestins upon activation, leading to receptor desensitization, internalization, and potentially G protein-independent signaling [1, 2].

Biased Agonism and Receptor Complexity

The ability of GHS-R1a to engage multiple signaling pathways opens the door for **biased agonism**. Different ligands (agonists, antagonists, or inverse agonists) can preferentially activate or inhibit specific downstream pathways (e.g., favoring G protein signaling over β-arrestin recruitment, or vice versa). This offers the potential to develop drugs with more targeted effects and potentially fewer side effects compared to non-biased ligands [1, 2]. For example, a biased agonist might stimulate pathways relevant to metabolic benefits while avoiding those causing unwanted GH release.

GHS-R1a function is further complicated by its tendency to form **dimers**, both with itself (homodimers) and with other receptors (heterodimers). Heterodimerization has been reported with the inactive GHS-R1b splice variant, dopamine receptors (DRD1, DRD2), serotonin receptor (5-HT2c), and melanocortin receptor (MC3R) [1, 2]. These interactions can alter ligand binding, signaling properties, and receptor trafficking, adding another layer of regulatory complexity and presenting potential novel therapeutic targets [2]. Additionally, accessory proteins like MRAP2 can modulate GHS-R1a signaling, potentiating Gαq/11 pathways while inhibiting constitutive activity and β-arrestin recruitment [1].

References

[1] Giorgioni, G., et al. (2022). Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor. *Journal of medicinal chemistry*, *65*(5), 3796–3830. PMC8883476

[2] Müller, T. D., et al. (2020). Ghrelin signaling: GOAT and GHS-R1a take a LEAP in complexity. *Endocrinology*, *161*(7), bqaa061. PMC7299083