Introduction: Low voltage-activated T-type calcium channels (T-type I_Ca), Ca_V3.1, Ca_V3.2, and Ca_V3.3 are opened by small depolarizations from the resting membrane potential in many cells and have been associated with neurological disorders including absence epilepsy and pain. Δ⁹-tetrahydrocannabinol (THC) is the principal psychoactive compound in Cannabis and also directly modulates T-type I_Ca , however, there is no information about functional activity of most phytocannabinoids on T-type I_Ca, including Δ⁹-tetrahydrocannabinol acid (THCA), the natural non-psychoactive precursor of THC. The aim of this work was to characterize THCA effects on T-type I_Ca . Materials and Methods: We used HEK293 Flp-In-TREx cells stably expressing Ca_V3.1, 3.2 or 3.3. Whole-cell patch clamp recordings were made to investigate cannabinoid modulation of I_Ca . Results: THCA and THC inhibited the peak current amplitude Ca_V3.1 with a pEC50s of 6.0 ± 0.7 and 5.6 ± 0.4, respectively. 1 μM THCA or THC produced a significant negative shift in half activation and inactivation of Ca_V3.1 and both drugs prolonged Ca_V3.1 deactivation kinetics. THCA (10 μM) inhibited Ca_V3.2 by 53% ± 4 and both THCA and THC produced a substantial negative shift in the voltage for half inactivation and modest negative shift in half activation of Ca_V3.2. THC prolonged the deactivation time of Ca_V3.2 while THCA did not. THCA inhibited the peak current of Ca_V3.3 by 43% ± 2 (10μM) but did not notably affect Ca_V3.3 channel activation or inactivation, however, THC caused significant hyperpolarizing shift in Ca_V3.3 steady state inactivation. Discussion: THCA modulated T-type I_Ca currents in vitro, with significant modulation of kinetics and voltage dependence at low μM concentrations. This study suggests that THCA may have potential for therapeutic use in pain and epilepsy via T-type channel modulation without the unwanted psychoactive effects associated with THC

中文翻译：

---

Δ9-四氢大麻酚酸对重组人T型钙通道的调节

简介：低电压激活的T型钙通道（T I型_Ca），Ca _V 3.1，Ca _V 3.2和Ca _V 3.3通过许多细胞中静息膜电位的小的去极化作用而打开，并且与神经系统疾病有关失神包括癫痫和疼痛。Δ ⁹ -四氢大麻酚（THC）是大麻的主要的对精神化合物，并且还直接调制的T型我_的Ca ，但是，没有关于对T型最phytocannabinoids的功能活性信息我_的Ca，包括Δ ⁹-四氢大麻酚酸（THCA），THC的天然非精神活性前体。这项工作的目的是表征THCA对T型I _Ca的影响 。材料和方法：我们使用稳定表达Ca _V 3.1、3.2或3.3的HEK293 Flp-In-TREx细胞。全细胞膜片钳记录作了调查的大麻素调节我_钙 。结果： THCA和THC抑制了峰值电流幅度Ca _V 3.1，pEC50分别为6.0±0.7和5.6±0.4。1μMTHCA或THC在Ca _V 3.1的半激活和灭活中产生了显着的负向偏移，并且两种药物均延长了Ca _V3.1失活动力学。THCA（10μM）将Ca _V 3.2抑制了53％±4，并且THCA和THC均使Ca _V 3.2的一半灭活产生了电压的显着负移，而在Ca _V 3.2的一半激活发生了适度的负移。THC延长了Ca _V 3.2的失活时间，而THCA却没有。THCA将Ca _V 3.3的峰值电流抑制了43％±2（10μM），但没有显着影响Ca _V 3.3通道的激活或失活，但是THC在Ca _V 3.3稳态失活中引起了明显的超极化位移。讨论： THCA调制的T型I _Ca在低μM浓度下具有明显的动力学和电压依赖性调节作用。这项研究表明，THCA可能具有通过T型通道调节作用治疗疼痛和癫痫的潜力，而不会产生与THC相关的不良心理作用