Bubien J K, Ismailov I I, Berdiev B K, Cornwell T, Lifton R P, Fuller C M, Achard J M, Benos D J, Warnock D G
Department of Medicine, University of Alabama at Birmingham, USA.
Am J Physiol. 1996 Jan;270(1 Pt 1):C208-13. doi: 10.1152/ajpcell.1996.270.1.C208.
Liddle's disease is an autosomal dominant genetic disorder characterized by severe low renin hypertension ("pseudoaldosteronism") that has been genetically linked to a locus on chromosome 16 encoding the beta-subunit of an amiloride-sensitive Na+ channel (ASSC) (15). Peripheral blood lymphocytes (PBL) express ASSC that are functionally indistinguishable from those expressed by Na(+)-reabsorbing renal epithelial cells (3, 5). The amiloride-sensitive Na+ conductance in PBL from affected and unaffected individuals from the original Liddle's pedigree was examined using whole cell patch clamp. Typically, the basal Na+ currents in cells from affected individuals were maximally activated. Basal Na+ currents in cells from unaffected individuals were minimal and could be maximally activated by superfusion with 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate (CPT-cAMP). Affected cells could not be further stimulated with CPT-cAMP. Superfusion with a supermaximal concentration of amiloride (2 microM) inhibited both the cAMP-activated Na+ conductance in unaffected cells and the constitutively activated inward conductance in affected cells. Cytosolic addition of a peptide identical to the terminal 10 amino acids of the truncated beta-subunit normalized the cAMP-mediated but not the pertussis toxin-induced regulation of the mutant ASSC. The findings show that lymphocyte ASSC are constitutively activated in affected individuals, that a mutation of the beta-subunit alters ASSC responsiveness to specific regulatory effectors, and that the cellular mechanism responsible for the pathophysiology of Liddle's disease is abnormal regulation of Na+ channel activity. These findings have important diagnostic and therapeutic implications and provide a cellular phenotype for the diagnosis of pseudoaldosteronism.
利德尔综合征是一种常染色体显性遗传病，其特征为严重的低肾素性高血压（“假性醛固酮增多症”），该病症在基因上与16号染色体上一个编码氨氯地平敏感钠通道（ASSC）β亚基的位点相关联（15）。外周血淋巴细胞（PBL）表达的ASSC在功能上与钠重吸收肾上皮细胞所表达的ASSC无法区分（3,5）。使用全细胞膜片钳技术检测了来自原始利德尔家系中患病和未患病个体的PBL中的氨氯地平敏感钠电导。通常，患病个体细胞中的基础钠电流被最大程度激活。未患病个体细胞中的基础钠电流最小，并且通过用8 -（4 - 氯苯硫基）腺苷3'，5'-环磷酸（CPT - cAMP）灌注可被最大程度激活。患病细胞不能被CPT - cAMP进一步刺激。用超最大浓度的氨氯地平（2 microM）灌注可抑制未患病细胞中cAMP激活的钠电导以及患病细胞中组成性激活的内向电导。向胞质中添加与截短的β亚基末端10个氨基酸相同的肽可使cAMP介导的但不是百日咳毒素诱导的突变ASSC调节正常化。这些发现表明，在患病个体中淋巴细胞ASSC被组成性激活，β亚基的突变改变了ASSC对特定调节效应物的反应性，并且利德尔综合征病理生理学的细胞机制是钠通道活性的异常调节。这些发现具有重要的诊断和治疗意义，并为假性醛固酮增多症的诊断提供了一种细胞表型。
