Sex specific association of potassium channel subunits.
Sex specific association of potassium channel subunits.
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钾通道亚基的性别特异性关联。
DOI：
10.1113/jphysiol.2011.221630
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Bett,GlennaCL
中科院分区：
文献类型：
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作者：
Duffey,MichaelE;Bett,GlennaCL
性激素在KCNE钾通道亚基的历史中发挥了重要作用。KCNE亚基最初被发现是从子宫肌肉中分离的经尿道调节的钾通道组分（Pragnell et al. 1990）。尽管如此，性激素和性别差异在非性腺组织中KCNE表达和功能中的作用仍然相对未被探索。尽管最初被误认为是“MinK”（一种独立的成孔亚基），但现在已知KCNE 1和KCNE家族是辅助亚基，对钾通道伴侣的稳定性和生物物理行为具有显着影响（Bett & Rasmusson，2008）。KCNE亚基是相对小的57-150个氨基酸的蛋白质，其跨越具有细胞外N-末端和细胞内C-末端的膜。已知KCNE 1和KCNE 3与电压门控钾通道KCNQ 1（KvLQT 1，Kv 7. 1）。电生理记录的KCNQ 1电流的组织特异性特征是多样的，由于这些辅助亚基对KCNQ 1的强烈修饰。KCNE 1/KCNQ 1组件产生非常缓慢的激活和去激活电流。相比之下，KCNE 3/KCNQ 1组装产生具有非常小的电压依赖性门控的组成性活性电流。在离子通道领域普遍接受的是，KCNQ 1和KCNE 3在结肠上皮中共组装形成组成型开放钾通道，作为控制液体分泌的基底外侧膜钾电流的基础（Schroeder et al. 2000）。KCNQ 1/KCNE 3的最初研究几乎仅在雄性动物中进行。在最近一期《生理学杂志》上发表的一项关于大鼠结肠两性异形的优雅研究中，（2011）在雄性大鼠中证实了这一发现，但令人惊讶的是，这只适用于雄性动物，而不是雌性动物。Alzamoraet al.证明了雄性和雌性之间通道蛋白的表达存在性别差异，而且相对表达差异在发情周期中发生变化。Alzamora等人还证明了KCNQ 1和KCNE 3之间相互作用的短期激素调节，因为雌激素似乎使KCNE 3与KCNQ 1解偶联，但不影响KCNQ 1和KCNE 1的相互作用。这是一个非常重要的发现，因为辅助亚基表达可以显著影响通道特性，并改变电流大小、门控动力学和药理学敏感性。事实上，Alzamora等人，证实了对色原烷醇293 B的敏感性的10倍性别依赖性变化：在雄性色原烷醇293 B的IC 50药物浓度下，该药物对雌性结肠几乎没有影响。
Sex hormones have played a strong role in the history of KCNE potassium channel subunits. KCNE subunits were originally discovered as hormonally regulated potassium channel components isolated from uterine muscle (Pragnell et al. 1990). Despite this, the role that sex hormones and sex differences play in KCNE expression and function in non-gonadal tissues has remained relatively unexplored. Although initially misidentified as ‘MinK’, an independent pore forming subunit, KCNE1 and the KCNE family are now known to be ancillary subunits with significant influence on the stability and biophysical behaviour of potassium channel partners (Bett & Rasmusson, 2008). KCNE subunits are relatively small 57–150-amino-acid proteins that span the membrane with an extracellular N-terminal and an intracellular C-terminal. KCNE1 and KCNE3 are known to associate with the voltage-gated potassium channel KCNQ1 (KvLQT1, Kv7. 1). The tissue-specific characteristics of electrophysiologically recorded KCNQ1 current are diverse, due to strong modification of KCNQ1 by these ancillary subunits. The KCNE1/KCNQ1 assembly produces a very slowly activating and deactivating current. In contrast, the KCNE3/KCNQ1 assembly produces a constituitively active current with very little voltage-dependent gating. It is commonly accepted in the field of ion channels that KCNQ1 and KCNE3 co-assemble in the epithelium of the colon to form a constitutively open potassium channel, underlying the basolateral membrane potassium current which controls fluid secretion (Schroeder et al. 2000). The initial studies of KCNQ1/KCNE3 were performed almost exclusively on male animals. In an elegant study on sexual dimorphism in rat colon in a recent issue of The Journal of PhysiologyAlzamora et al.(2011) confirm this finding in male rats, but surprisingly show that this is true only in male animals, not female animals. Alzamoraet al. demonstrate that there are sex differences in the expression of the channel proteins between males and females, and furthermore that the relative expression differences change during the oestrous cycle. Alzamora et al. also demonstrate the short term hormonal regulation of the interaction between KCNQ1 and KCNE3, as oestrogen appears to uncouple KCNE3 from KCNQ1 but does not affect the interaction of KCNQ1 and KCNE1. This is a very significant finding since ancillary subunit expression can dramatically affect channel properties, and alter current magnitude, gating kinetics and pharmacological sensitivity. Indeed, Alzamora et al., demonstrate a 10 fold sex dependent change in the sensitivity to chromanol 293B: At the IC50 drug concentrations for chromanol 293B in males, the drug barely has an effect on the female colon.