Park Yong Soo, Kim Gyu Min, Sung Ho Jun, Yu Ju Yeong, Sung Ki-Wug
Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
Korean J Physiol Pharmacol. 2025 May 1;29(3):373-384. doi: 10.4196/kjpp.24.363. Epub 2024 Dec 18.
The 5-hydroxytryptamine type (5-HT) receptor, a ligand-gated ion channel, plays a critical role in synaptic transmission. It has been implicated in various neuropsychiatric disorders. This study aimed to elucidate the mechanism by which quetiapine, an atypical antipsychotic, could inhibit 5-HT receptor-mediated currents in NCB20 neuroblastoma cells. Whole-cell patch-clamp recordings were used to study effects of quetiapine on receptor ion channel kinetics and its competitive antagonism. Co-application of quetiapine shifted 5-HT concentration-response curve rightward, significantly increasing the EC50 without altering the maximal response (E), suggesting a competitive inhibition. Quetiapine's IC varied with 5-HT concentration and treatment condition. The IC value of quetiapine was 0.58 μM with 3 μM 5-HT and 25.23 μM with 10 μM 5-HT, indicating an inverse relationship between quetiapine efficacy and agonist concentration. Pretreatment of quetiapine significantly enhanced its inhibitory potency, reducing its IC from 25.23 μM to 0.20 μM. Interaction kinetics experiments revealed an IC of 5.17 μM for an open state of the 5-HT receptor, suggesting weaker affinity during receptor activation. Quetiapine also accelerated receptor deactivation and desensitization, suggesting that it could stabilize the receptor in non-conducting states. Additionally, quetiapine significantly prolonged recovery from desensitization without affecting recovery from deactivation, demonstrating its selective impact on receptor kinetics. Inhibition of the 5-HT receptor by quetiapine was voltage-independent, and quetiapine exhibited no use-dependency, further supporting its role as a competitive antagonist. These findings provide insights into inhibitory mechanism of quetiapine on 5-HT receptor and suggest its potential therapeutic implications for modulating serotonergic pathways in neuropsychiatric disorders.
5-羟色胺（5-HT）受体作为一种配体门控离子通道，在突触传递中起关键作用。它与多种神经精神疾病有关。本研究旨在阐明非典型抗精神病药物喹硫平抑制NCB20神经母细胞瘤细胞中5-HT受体介导电流的机制。采用全细胞膜片钳记录来研究喹硫平对受体离子通道动力学及其竞争性拮抗作用的影响。喹硫平与5-HT共同应用使5-HT浓度-反应曲线右移，显著增加了半数有效浓度（EC50），但未改变最大反应（E），提示为竞争性抑制。喹硫平的半数抑制浓度（IC）随5-HT浓度和处理条件而变化。在3 μM 5-HT时喹硫平的IC值为0.58 μM，在10 μM 5-HT时为25.23 μM，表明喹硫平的效能与激动剂浓度呈反比关系。喹硫平预处理显著增强了其抑制效力，使其IC从25.23 μM降至0.20 μM。相互作用动力学实验显示，5-HT受体开放状态下喹硫平的IC为5.17 μM，提示受体激活过程中亲和力较弱。喹硫平还加速了受体失活和脱敏，表明它可使受体稳定在非传导状态。此外，喹硫平显著延长了脱敏后的恢复时间，而不影响失活后的恢复，证明了其对受体动力学的选择性影响。喹硫平对5-HT受体的抑制作用不依赖电压，且喹硫平无使用依赖性，进一步支持了其作为竞争性拮抗剂的作用。这些发现为喹硫平对5-HT受体的抑制机制提供了见解，并提示了其在调节神经精神疾病中血清素能通路方面的潜在治疗意义。
