GABRP encodes the pi subunit of GABA(A) receptors, heteropentameric ligand-gated chloride channels that mediate inhibitory neurotransmission. When activated by GABA, these channels allow selective chloride ion flow across cell membranes. Pi-containing GABA(A) receptors are predominantly expressed in peripheral tissues, where they modulate uterine contraction by altering sensitivity to pregnanolone and contribute to pulmonary chloride transport. Recent evidence reveals a non-canonical role for GABRP in cancer. GABRP is markedly overexpressed in pancreatic, colorectal, breast, and gastric cancers, where it drives tumor progression through multiple mechanisms. In pancreatic cancer, GABRP interacts with KCNN4 to induce calcium entry and activate NF-κB signaling, promoting chemokine expression and macrophage recruitment 1. A 2025 structural study demonstrates that GABRP homopentamers activate G-protein-coupled ERK signaling at physiological GABA concentrations, functioning analogously to metabotropic receptors rather than ionotropic chloride channels 2. In gliomas and other cancers, GABRP facilitates immune evasion by promoting GABA overproduction, which recruits immunosuppressive Tregs and M2 macrophages 3. GABRP also promotes gemcitabine resistance in pancreatic cancer via CD44-mediated pathways 4. Clinically, GABRP overexpression associates with poor prognosis and chemoresistance across multiple cancer types. Pharmacological GABA(A) inhibition (Amentoflavone) significantly reduces tumor burden and restores antitumor immunity, suggesting GABRP as a targetable mechanism for cancer therapy.