Gamma-aminobutyric acid-B receptor axis promotes proliferation and survival of multiple myeloma cells via enhancing ERK1/2 activity

Abstract Gamma-aminobutyric acid (GABA), a non-protein component amino acid, functions as an inhibitory neurotransmitter. Here, we showed that GABA levels are significantly elevated in the bone marrow (BM) liquid of patients with multiple myeloma (MM) compared to healthy donors (HDs). Moreover, BM GABA levels correlated with key clinical parameters, including plasma cell percentage, International Staging System (ISS) stage, and immunoglobulin subtype, highlighting its association with disease severity. Mechanistically, we identified glutamic acid decarboxylase 1 (GAD1) as a critical enzyme driving intracellular GABA production in MM cells, which promotes the survival and proliferation of MM cells. Additionally, GAD1-dependent GABA production supported MM progression by activating the GABA B receptor, as demonstrated in vitro and in vivo, underscoring the pivotal role of this receptor axis. Further mechanistic investigations revealed that the GABA-B receptor axis enhances ERK1/2 activity via cAMP downregulation, facilitating MM cell survival and proliferation. Taken together, our findings establish the GABA-B receptor-ERK1/2 axis as a central regulator of MM progression and propose it as a promising target for MM therapy.