Padín Juan Fernando, Fernández-Morales José-Carlos, de Diego Antonio M G, García Antonio G
Instituto Teófilo Hernando; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain.
Curr Mol Pharmacol. 2015;8(1):81-6. doi: 10.2174/1874467208666150507094537.
Here we review the contribution of the various subtypes of voltage-activated calcium channels (VACCs) to the regulation of catecholamine release from chromaffin cells (CCs) at early life. Patch-clamp recording of inward currents through VACCs has revealed the expression of high-threshold VACCs (high-VACCs) of the L, N, and PQ subtypes in rat embryo CCs and ovine embryo CCs. Low-threshold VACC (low-VACC) currents (T-type) have also been recorded in rat embryo CCs and rat neonatal slices of adrenal medullae. Near full blockade by nifedipine and nimodipine of the K(+)-elicited secretion as well as the hypoxia induced secretion (HIS) supports the dominant role of L-VACC subtypes to the regulation of exocytosis at early life. Partial blockade by ω-conotoxin GVIA and ω-agatoxin IVA suggests a transient participation of N and PQ high-VACCs to the regulation of the HIS response at early stages of CC exposure to hypoxia. T-type low-VACC current did not elicit exocytosis triggered by electrical depolarising pulses applied to rat embryo CCs in one study, but largely contributed to the HIS response in neonatal rat adrenal slices in another. In spite of scarce available data, the sequence of events driving the HIS response in CCs at early life could be established as follows: (i) hypoxia blocks one or more K(+) channels; (ii) as a consequence, mild membrane depolarisation occurs; (iii) T-type low-VACCs open at membrane potentials more hyperpolarised than those required to recruit the high-VACCs; (iv) firing of action potentials then occurs; (v) fast-inactivating N and PQ high-VACCs transiently open and low-inactivating L high-VACCs remain open along the hypoxia stimulus; (vi) increase of cytosolic Ca(2+) takes place; and (vii) the exocytotic release of catecholamine occurs in two phases, an explosive initial phase, driven by Ca(2+) entry through L, N and PQ channels, followed by a more sustained catecholamine release at a slower rate driven by L-type channels.
在此，我们回顾电压门控钙通道（VACCs）的各种亚型在生命早期对嗜铬细胞（CCs）儿茶酚胺释放调节的作用。通过VACCs记录内向电流的膜片钳技术揭示了大鼠胚胎CCs和绵羊胚胎CCs中L、N和PQ亚型的高阈值VACCs（高VACCs）的表达。在大鼠胚胎CCs和大鼠肾上腺髓质新生切片中也记录到了低阈值VACC（低VACC）电流（T型）。硝苯地平和尼莫地平对K⁺诱导分泌以及缺氧诱导分泌（HIS）的近乎完全阻断，支持了L - VACC亚型在生命早期对胞吐作用调节中的主导作用。ω - 芋螺毒素GVIA和ω - 阿加毒素IVA的部分阻断表明，在CCs暴露于缺氧的早期阶段，N和PQ高VACCs对HIS反应的调节有短暂参与。在一项研究中，T型低VACC电流并未引发施加于大鼠胚胎CCs的电去极化脉冲触发的胞吐作用，但在另一项研究中，它在新生大鼠肾上腺切片的HIS反应中起了很大作用。尽管现有数据稀少，但生命早期CCs中驱动HIS反应的事件序列可确定如下：（i）缺氧阻断一个或多个K⁺通道；（ii）结果，发生轻度膜去极化；（iii）T型低VACCs在比招募高VACCs所需的膜电位更超极化时开放；（iv）然后发生动作电位发放；（v）快速失活的N和PQ高VACCs短暂开放，而低失活的L高VACCs在缺氧刺激期间保持开放；（vi）胞质Ca²⁺增加；（vii）儿茶酚胺的胞吐释放分两个阶段发生，一个由通过L、N和PQ通道的Ca²⁺内流驱动的爆发性初始阶段，随后是由L型通道以较慢速率驱动的更持续的儿茶酚胺释放。
