Department of Otolaryngology-Head & Neck Surgery, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Int J Mol Sci. 2024 Aug 13;25(16):8801. doi: 10.3390/ijms25168801.
Previous studies have suggested a role for selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac) in the treatment of dizziness and inner ear vestibular dysfunction. The potential mechanism of action within the vestibular system remains unclear; however, fluoxetine has been reported to block certain types of K channel in other systems. Here, we investigated the direct actions of fluoxetine on membrane currents in presynaptic hair cells and postsynaptic calyx afferents of the gerbil peripheral vestibular system using whole cell patch clamp recordings in crista slices. We explored differences in K currents in peripheral zone (PZ) and central zone (CZ) calyces of the crista and their response to fluoxetine application. Outward K currents in PZ calyces showed greater inactivation at depolarized membrane potentials compared to CZ calyces. The application of 100 μM fluoxetine notably reduced K currents in calyx terminals within both zones of the crista, and the remaining currents exhibited distinct traits. In PZ cells, fluoxetine inhibited a non-inactivating K current and revealed a rapidly activating and inactivating K current, which was sensitive to blocking by 4-aminopyridine. This was in contrast to CZ calyces, where low-voltage-activated and non-inactivating K currents persisted following application of 100 μM fluoxetine. Additionally, marked inhibition of transient inward Na currents by fluoxetine was observed in calyces from both crista zones. Different concentrations of fluoxetine were tested, and the EC values were found to be 40 µM and 32 µM for K and Na currents, respectively. In contrast, 100 μM fluoxetine had no impact on voltage-dependent K currents in mechanosensory type I and type II vestibular hair cells. In summary, micromolar concentrations of fluoxetine are expected to strongly reduce both Na and K conductance in afferent neurons of the peripheral vestibular system in vivo. This would lead to inhibition of action potential firing in vestibular sensory neurons and has therapeutic implications for disorders of balance.
先前的研究表明，选择性 5-羟色胺再摄取抑制剂（SSRIs），如氟西汀（百忧解），在治疗头晕和内耳前庭功能障碍方面可能具有作用。然而，其在前庭系统中的潜在作用机制尚不清楚；但是，氟西汀已被报道在其他系统中阻断某些类型的 K 通道。在这里，我们使用在耳石切片上进行的全细胞膜片钳记录，研究了氟西汀对沙鼠外周前庭系统中突触前毛细胞和突触后壶腹传入的直接作用。我们探索了耳石外周区（PZ）和中央区（CZ）壶腹中的 K 电流的差异，以及它们对氟西汀应用的反应。与 CZ 壶腹相比，PZ 壶腹的外向 K 电流在去极化膜电位下表现出更大的失活。应用 100μM 氟西汀显著减少了耳石中两个区的钙末端的 K 电流，而剩余的电流表现出明显的特征。在 PZ 细胞中，氟西汀抑制了非失活的 K 电流，并揭示了一种快速激活和失活的 K 电流，该电流对 4-氨基吡啶敏感。这与 CZ 壶腹形成对比，在应用 100μM 氟西汀后，低电压激活和非失活的 K 电流持续存在。此外，在耳石中还观察到氟西汀对瞬态内向 Na 电流的显著抑制。测试了不同浓度的氟西汀，发现 K 和 Na 电流的 EC 值分别为 40μM 和 32μM。相比之下，100μM 氟西汀对机械感觉 I 型和 II 型前庭毛细胞的电压依赖性 K 电流没有影响。总之，毫摩尔浓度的氟西汀有望强烈降低外周前庭系统传入神经元中的 Na 和 K 电导。这将导致前庭感觉神经元中动作电位的发射受到抑制，对平衡障碍具有治疗意义。
