Elucidation of roles and development of selective blockers for novel voltage-gated Ca2+ channels in peripheral resistant arterioles

我们最近发现，在主要参与血压和循环调节的外周阻力小动脉中，主要存在硝苯地平不敏感（NI-CC）电压依赖性Ca ~（2+）通道（VDCCs），其生物物理和药理特性与迄今已知的VDCCs完全不同。外周循环中的NICC密度似乎朝向外周显著增加，几乎达到100%。在本研究中，我们阐明了以下几点：（1）NI-CC在大鼠和家兔的相同区域显示出与豚鼠肠系膜终末动脉几乎相同的特性;（2）NI-CC接受主要交感神经递质ATP的有效调节，在低和高ATP浓度下，蛋白激酶A和C分别通过通道蛋白磷酸化增强和抑制NI-CC活性。(3)加压条件下的小动脉直径或张力似乎至少部分由通过NI-CC的Ca 2+进入维持。(4)在目前可用的肽（ω-contoxin GVIA、MVIIC、ω-agatoxin IVA、SNX 482、sFTX 3.3）和VDCC的化学阻断剂中，只有米贝拉地尔（Ro 40 -5967 ; F-Hoffman La Roche）和芳基哌啶衍生物（Snp 200001、200002、200003 ; Suntory）在微摩尔浓度下完全抑制NI-CC电流。然而，这些效应对其他类型的VDCC（如T型和R型VDCC）是非特异性的，IC 50值不是后两种VDCC的三倍。从天然蛇类毒素中筛选出的NI-CC特异性阻断肽尚未成功获得，今后的研究工作将扩展到昆虫和海洋毒素。

We have recently found that in peripheral resistant arterioles which mainly contribute to regulating the blood pressure and circulation, nifedipine-insensitive (NI-CC) voltage-dependent Ca2+ channels (VDCCs) having entirely distinct biophysical and pharmacological properties from those of hitherto-known VDCCs predominantly exist. The density of NICCs in peripheral circulation appears to increase dramatically towards the periphery, reaching almost 100 %. In this study, we have clarified the following points about these NI-CCs :(1)NI-CCs showing almost identical properties to those in guinea-pig mesenteric terminal artery have been identified in the same regions of rat and rabbit,(2) NI-CCs undergo the effective regulation of a major sympathetic neurotransmitter ATP, which potentiates and inhibits NI-CC activities through channel protein phosphorylation by protein kinases A and C at low and higher ATP concentrations, respectively.(3) Arteriolar diameter or tone under pressurized conditions appears to be at least in part maintained by Ca2+ entry through NI-CC.(4) Amongst peptide (w-contoxin GVIA, MVIIC, w-agatoxin IVA, SNX482, sFTX3.3) and chemical blockers for VDCCs that are available at present, only mibefradil (Ro40-5967 ; F-Hoffman La Roche) and arylpiperadine derivatives (Snp200001,200002,200003 ; Suntory) completely suppressed NI-CC currents at micromolar concentrations. However, these effects are nonspecific to other types of VDCCs such as T- and R-type VDCCs, the IC50 values being not as three times low as those for the latter two VDCCs. New peptide bloekers selective for NI-CC have not yet been successfully obtained from the screening of natural toxins of snakes, the efforts will be extended to insect and marine toxins in future investigations.