FAM237A

FAM237A encodes a preprohormone that is post-translationally processed via C-terminal cleavage and amidation into a mature ~9 kDa secreted neuropeptide that functions as the primary endogenous agonist of the orphan GPCR GPR83 (PMID:32713278). Mature FAM237A binds GPR83 with nanomolar affinity, induces β-arrestin recruitment, and triggers receptor internalization (PMID:36853120).

1. 2020 Medium

   Establishing that the FAM237A gene product is not merely a precursor but undergoes regulated secretory pathway processing to yield a C-terminally amidated ~9 kDa neuropeptide that specifically activates the orphan receptor GPR83 resolved the ligand identity question for this brain-enriched GPCR.

   Evidence Functional GPCR screen using endocrine host cells co-expressing preprohormones with biochemical characterization of the processed form

   PMID:32713278

   Open questions at the time

   • Single-lab discovery without independent replication at the time
   • Downstream signaling cascades beyond GPCR activation not characterized
   • In vivo physiological relevance of the FAM237A–GPR83 axis not demonstrated
2. 2023 High

   Quantitative binding and functional assays confirmed FAM237A as the primary endogenous ligand for GPR83 — not PEN or proCCK56-63 — and revealed a complete agonist profile including nanomolar binding, β-arrestin recruitment, and receptor internalization, consolidating the deorphanization.

   Evidence NanoBiT-based ligand-binding, β-arrestin recruitment, and fluorescent ligand internalization assays with negative-control peptides in HEK293T cells

   PMID:36853120

   Open questions at the time

   • G-protein coupling specificity (Gi, Gq, Gs) of GPR83 upon FAM237A binding not determined
   • Endogenous tissue-level confirmation of the interaction (e.g., in hypothalamic neurons) not yet reported
   • Structural basis of FAM237A–GPR83 recognition unknown

• The in vivo physiological functions mediated by the FAM237A–GPR83 signaling axis — including roles in energy homeostasis, neuroendocrine regulation, or immune modulation — remain uncharacterized at the mechanistic level.
• No loss-of-function or gain-of-function animal models reported for FAM237A
• G-protein coupling pathway and downstream transcriptional consequences undefined
• Whether FAM237A signals through additional receptors beyond GPR83 is untested