PTH2R

PTH2R is a class B G protein-coupled receptor activated by its endogenous ligand TIP39 that transduces signals through intracellular calcium and cAMP/MAPK pathways to regulate cell differentiation, neuronal excitability, and glutamatergic neurotransmission. In keratinocytes, TIP39–PTH2R signaling elevates intracellular calcium and promotes terminal differentiation, with PTH2R knockout mice displaying increased epidermal thickness (PMID:27000502). In hippocampal CA1 neurons, adenylyl cyclase 8 maintains PTH2R expression via the MAPK pathway; loss of PTH2R reduces neuronal excitability and glutamatergic transmission, producing depressive-like behavior that is rescued by PTH2R overexpression or chronic TIP39 infusion (PMID:41387170).

1. 2011 Medium

   Establishing that pth2 ligand expression in the vertebrate CNS is regulated by hedgehog signaling and that pth2r is broadly co-expressed in the brain and otic vesicles placed the TIP39–PTH2R axis within a developmental signaling hierarchy.

   Evidence Hedgehog-pathway zebrafish mutant analysis with in situ hybridization expression mapping

   PMID:21880859

   Open questions at the time

   • Whether Hh regulation of PTH2 ligand is conserved in mammals is untested
   • Functional consequence of pth2r expression in otic vesicles is unknown
   • Downstream signaling pathway activated by Pth2r in the developing CNS was not examined
2. 2016 Medium

   Demonstrating that TIP39 activates PTH2R at the keratinocyte membrane to elevate intracellular calcium and drive terminal differentiation—confirmed by epidermal thickening in PTH2R knockout mice—established a non-neuronal physiological function for this receptor.

   Evidence Recombinant TIP39 stimulation of human keratinocytes with calcium and differentiation marker readouts; PTH2R−/− mouse phenotyping

   PMID:27000502

   Open questions at the time

   • Single-lab study; independent replication not available
   • The downstream signaling cascade between calcium elevation and involucrin induction was not mapped
   • Whether PTH2R signals through Gαs/cAMP or Gαq/calcium in keratinocytes was not dissected
3. 2021 Medium

   Identifying an enhancer element (rs13383928) that physically contacts the PTH2R promoter and is bound by FOXJ2 revealed a transcriptional regulatory mechanism controlling PTH2R expression in lung tissue.

   Evidence Dual luciferase enhancer assay, chromosome conformation capture (3C), and ChIP in lung cells

   PMID:33550301

   Open questions at the time

   • Functional consequence of altered PTH2R expression in lung physiology is unknown
   • Whether FOXJ2 regulation of PTH2R operates in other tissues was not tested
   • No knockout or knockdown of FOXJ2 was performed to confirm necessity
4. 2025 High

   Revealing that adenylyl cyclase 8 sustains PTH2R protein levels via MAPK signaling in hippocampal CA1 neurons, and that PTH2R is required for neuronal excitability and glutamatergic neurotransmission, connected the receptor to mood regulation and provided a complete loss-of-function/rescue circuit.

   Evidence Conditional Adcy8 knockout, AAV-shRNA Pth2r knockdown, PTH2R overexpression rescue, electrophysiology, and chronic TIP39 hippocampal infusion in mice

   PMID:41387170

   Open questions at the time

   • The specific MAPK pathway member(s) that regulate PTH2R transcription or stability are not identified
   • Whether PTH2R acts through Gαs-cAMP or alternative effectors in hippocampal neurons is unresolved
   • Relevance to human depression has not been demonstrated

• The intracellular signaling effectors (specific G-protein coupling, second messengers) directly activated by PTH2R in neurons and other tissues, and the structural basis of TIP39 selectivity for PTH2R over PTH1R, remain uncharacterized by direct experimental evidence.
• No G-protein coupling selectivity data from reconstituted systems
• No structural model of the TIP39–PTH2R complex
• Physiological roles in lung and inner ear implied by expression data but not functionally tested