Pappas C A, Ritchie J M
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
Glia. 1998 Feb;22(2):113-20.
Mitogenesis in a variety of tissues is known to be inhibited by K+ channel blockers such as tetraethylammonium (TEA) and 4-aminopyridine (4-AP). Using radiolabeled thymidine as a proliferation index we have examined what role, if any, specific K+ channels have in cultured Schwann cells that have been induced to proliferate by pre-exposure to mitogens. TEA and 4-AP are "broad-spectrum" in that they block a variety of different types of K+ channel. In contrast, we found that alpha-dendrotoxin (alpha-DTX), a specific blocker of the type 1 fast delayed rectifier current (the largest component of Schwann cell K+ current) does not affect proliferation, suggesting that type 1 current may not be involved in mitogenesis. This suggestion is supported by our finding that the values of the KD for the mitogenic effect (722 nM, 4-AP; 13 mM, TEA) are much larger than the corresponding electrophysiological values for type 1 channels (0.1 mM, 4-AP; 0.2 mM, TEA). Charybdotoxin (200 nM) and iberiotoxin (100 nM), inhibitors of Ca2+-activated K+ channels, cesium (5 mM), an inhibitor of inward rectifier channels, and furosemide (100 pM), which blocks Na+/K+/Cl- cotransport, all had no effect on proliferation. Interestingly, 4,4'-diisothiocyanatostilbene 2,2'-disulphonate (DIDS), which blocks voltage-gated Cl- channels, reduced proliferation. In summary, broad-spectrum K+ channel blockers inhibit Schwann cell proliferation, but inhibitors specific for type 1, Ca2+-activated, and inward rectifier K+ channels do not. Whether the inhibition is mediated by type 2 K- channels, by an as yet unidentified Schwann cell K+ channel, or by another mechanism remains unclear.
已知钾离子通道阻滞剂如四乙铵（TEA）和4-氨基吡啶（4-AP）可抑制多种组织的有丝分裂。我们使用放射性标记的胸腺嘧啶核苷作为增殖指标，研究了特定钾离子通道在预先暴露于有丝分裂原后被诱导增殖的培养雪旺细胞中是否发挥作用（若有作用，则作用是什么）。TEA和4-AP具有“广谱性”，因为它们可阻断多种不同类型的钾离子通道。相比之下，我们发现α-树眼镜蛇毒素（α-DTX），一种1型快速延迟整流电流（雪旺细胞钾离子电流的最大组成部分）的特异性阻滞剂，并不影响增殖，这表明1型电流可能不参与有丝分裂。我们的这一推测得到了以下发现的支持：有丝分裂效应的KD值（4-AP为722 nM；TEA为13 mM）远大于1型通道相应的电生理值（4-AP为0.1 mM；TEA为0.2 mM）。大电导钙激活钾通道抑制剂毒胡萝卜素（200 nM）和埃博毒素（100 nM）、内向整流通道抑制剂铯（5 mM）以及阻断Na+/K+/Cl-协同转运的呋塞米（100 pM），均对增殖无影响。有趣的是，阻断电压门控氯离子通道的4,4'-二异硫氰酸芪-2,2'-二磺酸盐（DIDS）可降低增殖。总之，广谱钾离子通道阻滞剂可抑制雪旺细胞增殖，但1型、钙激活和内向整流钾离子通道的特异性抑制剂则无此作用。这种抑制是由2型钾通道介导，还是由尚未确定的雪旺细胞钾离子通道介导，抑或是由其他机制介导，目前尚不清楚。
