Verapamil Inhibits TRESK (K18.1) Current in Trigeminal Ganglion Neurons Independently of the Blockade of Ca Influx.

Tandem pore domain weak inward rectifier potassium channel (TWIK)-related spinal cord K⁺ (TRESK; K18.1) channel is the only member of the two-pore domain K⁺ (K) channel family that is activated by an increase in intracellular Ca concentration ([Ca]) and linked to migraines. This study was performed to identify the effect of verapamil, which is an L-type Ca channel blocker and a prophylaxis for migraines, on the TRESK channel in trigeminal ganglion (TG) neurons, as well as in a heterologous system. Single-channel and whole-cell currents were recorded in TG neurons and HEK-293 cells transfected with mTRESK using patch-clamping techniques. In TG neurons, changes in [Ca] were measured using the fluo-3-AM Ca indicator. Verapamil, nifedipine, and NiCl₂ inhibited the whole-cell currents in HEK-293 cells overexpressing mTRESK with IC values of 5.2, 54.3, and >100 μM, respectively. The inhibitory effect of verapamil on TRESK channel was also observed in excised patches. In TG neurons, verapamil (10 μM) inhibited TRESK channel activity by approximately 76%. The TRESK channel activity was not dependent on the presence of extracellular Ca. In addition, the inhibitory effect of verapamil on the TRESK channel remained despite the absence of extracellular Ca. These findings show that verapamil inhibits the TRESK current independently of the blockade of Ca influx in TG neurons. Verapamil will be able to exert its pharmacological effects by modulating TRESK, as well as Ca influx, in TG neurons in vitro. We suggest that verapamil could be used as an inhibitor for identifying TRESK channel in TG neurons.