TACR2

TACR2 encodes the NK2 receptor - the class A GPCR that mediates smooth muscle contraction and visceral hypersensitivity through preferential binding to neurokinin A (NKA). It is the dominant tachykinin receptor in gastrointestinal, airway, and urinary tract smooth muscle, driving bronchoconstriction, intestinal motility, and detrusor contraction. NK2R antagonists have been investigated in clinical trials for irritable bowel syndrome (ibodutant reached Phase 2) and asthma, but none are approved. Genetic variants in TACR2 associate with reduced BMI and fat percentage in human populations, revealing an emerging metabolic role. Every scaffold targeting neurogenic smooth muscle control, visceral pain, or peripheral tachykinin signaling routes through this card.

TACR2 (chromosome 10q22.1, 384 aa, 5 exons; α and β splice isoforms - β lacks part of ECL1) is a Gq/11-primary class A GPCR. NKA (His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH₂, 10 aa) is the highest-affinity endogenous agonist (Ki ~0.5 nM); neurokinin B binds at Ki ~5–10 nM; substance P at Ki ~100 nM. All tachykinins share the C-terminal Phe-X-Gly-Leu-Met-NH₂ pharmacophore essential for binding, but NK2R selectivity is conferred by NKA's Asp4, which forms a salt bridge with Arg197^{ECL2} in the receptor - a unique contact absent in the related NK1R (where Val occupies the equivalent ECL2 position). Cryo-EM structure of NK2R-Gq at 2.7 Å (PDB: 7XWO) defines the orthosteric pocket: TM2 (Tyr93, Asn90, Asn97), TM3 (Ile114), TM6 (Tyr266), TM7 (Tyr289, Ile285), and ECL2 (Asp175, Lys180) are key contacts. Signaling: Gq/11 → PLC-β → IP3/Ca²⁺ → smooth muscle contraction; Gs → cAMP at lower efficacy; β-arrestin-1 (EC₅₀ ~0.03 nM) → ERK/MAPK; C-terminal GRK phosphorylation → desensitization and internalization. NK2R upregulation occurs in the spinal cord dorsal horn during inflammatory pain and in the colon during IBD, contributing to central sensitization and mucosal inflammation respectively.

No NK2R antagonist is approved. Saredutant (SR 48968) is a high-affinity non-peptide antagonist (pKi ~9.4–9.7, Ki ~0.03 nM) that reached Phase 3 for major depressive disorder but failed efficacy endpoints and was discontinued in 2009. Nepadutant (MEN 11420, glycosylated cyclic peptide antagonist, Ki ~0.2–3 nM) showed IV proof-of-concept for NKA-induced intestinal motility. Ibodutant (MEN 15596) showed Phase 2 benefit in female diarrhea-predominant IBS-D but was discontinued ~2017. The selective agonist probe is [β-Ala⁸]NKA(4-10), a metabolically stable truncated analog (EC₅₀ ~1 nM). For peptide research, the tractable recipes are: NKA(4-10) truncation analogs with Aib or D-amino acid at position 5 (Val5) for protease resistance while maintaining high NK2R potency; ECL2-targeting cyclic peptide antagonists that exploit the Lys180–Asp4 interaction to achieve NK2R selectivity over NK1R; N-terminal NKA(1-3) extensions modified to engage the ECL2/N-terminal receptor vestibule for improved selectivity in airway vs. GI NK2R subtypes; and biased NK2R agonists that activate Gq/Ca²⁺ smooth muscle relaxation over β-arrestin-driven internalization for sustained intestinal motility modulation.