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

我们最近发现，在主要有助于调节血压和循环的外周耐药小动脉中，硝苯地平不敏感（NI-CC）电压依赖性Ca2+通道（vdcc）主要存在与迄今已知的vdcc具有完全不同的生物物理和药理学特性。外周循环中NICCs的密度似乎向外周急剧增加，几乎达到100%。在本研究中，我们明确了这些NI-CC的以下观点：(1)在大鼠和家兔的相同区域发现了与豚鼠肠系膜末端动脉中NI-CC几乎相同的特性；(2)NI-CC可以有效调节一种主要的交感神经递质ATP， ATP分别在低和高ATP浓度下通过蛋白激酶a和C磷酸化通道蛋白来增强和抑制NI-CC的活性。(3)加压条件下的动脉直径或张力似乎至少部分是通过NI-CC的Ca2+进入维持的。(4)在目前可用的多肽（w-contoxin GVIA， MVIIC, w-agatoxin IVA, SNX482, sFTX3.3）和vdccc化学阻滞剂中，只有米贝弗拉迪（Ro40-5967; F-Hoffman La Roche）和芳基哌拉定衍生物（Snp200001,200002,200003; Suntory）在微摩尔浓度下完全抑制NI-CC电流。然而，这些影响对其他类型的vdcs（如T型和r型vdcs）没有特异性，IC50值没有后两种vdcs低三倍。目前在蛇类天然毒素的筛选中尚未成功获得对NI-CC有选择性的新型肽阻断剂，今后的研究将扩大到昆虫和海洋毒素的筛选。

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.