The role of auxiliary GABAB receptor subunit KCTD16 in pain modulation

Abstract

Chronic pain affects nearly 10% of the global population and remains a major clinical challenge due to the limited efficacy and adverse effects of current therapies. In this study, we identify the potassium channel tetramerization domain protein KCTD16 as a key modulator of GABA_B receptor mediated inhibition of nociceptive transmission. Immunohistochemical analysis revealed prominent KCTD16 expression in dorsal horn and dorsal root ganglion (DRG) neurons, consistent with a role in spinal nociceptive processing. KCTD16 knockout (KO) mice exhibited increased mechanical thresholds relative to wild-type (WT) littermates, while thermal sensitivity remained unchanged; this phenotype persisted following carrageenan-induced inflammation. The GABA_B receptor agonist Baclofen produced strong analgesic effects in WT mice under both basal and inflammatory conditions, whereas its anti-allodynic efficacy was significantly reduced in KO animals. Whole-cell patch-clamp recordings from dorsal horn neurons showed comparable baseline miniature excitatory and lower inhibitory postsynaptic currents (mEPSCs and mIPSCs) for KCTD16^-/-. However, following inflammation, Baclofen-induced suppression of excitatory transmission was potentiated in WT but markedly attenuated in KO neurons. Light-evoked synaptic inhibitory currents and calcium imaging of cultured DRG neurons further demonstrated enhanced Baclofen sensitivity in WT cells. These findings indicate that KCTD16 plays a critical role in presynaptic modulation of inhibitory control in the spinal dorsal horn, affecting the balance between the excitation and inhibition in nociceptive circuits. Collectively, these results demonstrate that KCTD16 modulates GABA_B receptor-dependent inhibitory control of nociceptive signaling and highlight the GABA_B receptor-KCTD16 complex as a promising new molecular target for effective pain treatments.

Keywords: DRG neurons; GABA(B)R; Inflammation; KCTD16; Spinal cord; Synaptic transmission.