Beyond the one known ghrelin receptor, scientists found evidence for at least two additional classes of receptors that could explain many of ghrelin's wide-ranging effects in the body.
2+ novel receptor classesBeyond the known GHSR1a receptor, at least two additional types of ghrelin receptors appear to exist but remain molecularly unidentified
What the researchers found
Beyond the known ghrelin receptor GHSR1a, evidence points to at least two additional classes of receptors: ghrelin receptor-like receptors (GRLRs) that respond to both ghrelin and its unacylated form (UAG), and UAG-specific receptors that respond only to unacylated ghrelin. These novel receptors may be heterodimers formed when GHSR1a or GHSR1b pairs with other G protein-coupled receptors, creating complexes with distinct pharmacological properties.
Effects mediated through these novel receptors include fat cell lipid accumulation, muscle cell differentiation, bone cell proliferation, insulin release, heart protection, blood vessel constriction and growth, and tumor cell proliferation — none of which can be fully explained by GHSR1a alone.
Why it matters
Ghrelin is one of the most important peptide hormones in metabolism, appetite regulation, and growth hormone release. Discovering that it acts through multiple previously unknown receptors fundamentally expands our understanding of how this peptide works in the body and opens new therapeutic targets for conditions ranging from obesity to heart disease to cancer.
The numbers in context
1 known receptor (GHSR1a) · 2 proposed novel receptor classes (GRLRs, UAG receptors) · 1 identified novel receptor (CD36) · 8+ biological effects attributed to novel receptors
How the study worked
This was a comprehensive review of published literature critically evaluating evidence for ghrelin receptor ligand effects that cannot be explained by action at the known GHSR1a receptor. The authors analyzed studies involving receptor expression detection, gene knockout models, and competitive binding assays.
What this study cannot tell us
Most proposed novel receptors have not been molecularly identified, making it difficult to design targeted drugs. The heterodimer hypothesis, while plausible, remains largely unproven. Much of the evidence for novel receptors comes from indirect observations such as effects persisting after GHSR1a gene knockout rather than direct receptor identification.
How to read the evidence
This is a comprehensive narrative review published in Pharmacological Reviews, a high-impact journal. It synthesizes evidence from multiple study types but does not present new experimental data.
When this study was published
Published in 2014, this review established the framework for understanding ghrelin's multi-receptor signaling. Research into novel ghrelin receptors has continued since, though molecular identification of the proposed receptors remains an active challenge.
The bigger picture
Ghrelin-based therapies have been explored for appetite disorders, growth hormone deficiency, and gastroparesis, but results have been mixed — possibly because researchers were targeting only one of multiple receptors. This review suggests the ghrelin signaling system is far more complex than previously thought, which could explain why some ghrelin-based drugs have had limited success and point toward more precise therapeutic strategies.
Questions still open
- Can the proposed novel ghrelin receptors be molecularly identified and characterized for drug targeting?
- Do GHSR1a/GHSR1b heterodimers with other G protein-coupled receptors account for the unexplained effects of ghrelin?
- Could targeting UAG-specific receptors offer therapeutic benefits without the appetite-stimulating effects of ghrelin?
Common questions
What is ghrelin and why does it matter?
What is the difference between ghrelin and unacylated ghrelin (UAG)?
Read the original research
Novel and conventional receptors for ghrelin, desacyl-ghrelin, and pharmacologically related compounds.
Pharmacological reviews, 66(4), 984-1001
Citation
Callaghan, Brid; Furness, John B. (2014). Novel and conventional receptors for ghrelin, desacyl-ghrelin, and pharmacologically related compounds.. Pharmacological reviews, 66(4), 984-1001. https://doi.org/10.1124/pr.113.008433