Department of Physiology and Biophysics, School of Life Sciences, Institutes of Brain Science, Fudan University, Shanghai, China.
Department of Physiology and Biophysics, School of Life Sciences, Institutes of Brain Science, Fudan University, Shanghai, China.
Cell Calcium. 2019 Dec;84:102104. doi: 10.1016/j.ceca.2019.102104. Epub 2019 Nov 1.
Ca3.2 calcium channels play important roles in both neural excitability and aldosterone secretion. Recent clinical studies found four germline mutations (S196 L, M1549I, V1951E and P2083 L) in Ca3.2 channels. All four mutations caused primary aldosteronism (PA), while only the M1549I mutation resulted in obvious neural malfunctions besides PA. In human, there are two major Ca3.2 channel gene (CACNA1H) splice variants, either with or without exon 26. In this study, we tested the expression of the two CACNA1H splice variants in zona glomerulosa (ZG) cells of human adrenal cortex and the possibility that Ca3.2 (-26) and Ca3.2 (+26) channels have different functional responses to the four PA mutations. We found that human ZG cells only express long form Ca3.2(+26) channels. The M1549I mutation slowed the inactivation of Ca3.2(+26) more than 5 fold, and Ca3.2(-26) more than 2 fold. The S196 L, V1951E and P2083 L mutations accelerated channel recovery from inactivation for Ca3.2(+26), but not Ca3.2(-26) channels. All four mutations resulted in gain of function of Ca3.2(+26) channels, leading to overproduction of aldosterone. In conclusion, the four PA mutations caused more profound changes on Ca3.2 (+26) currents than on Ca3.2 (-26) currents, and except the M1549I mutation, the S196 L, V1951E and P2083 L have little effect on the electrophysiological properties of Ca3.2(-26) currents, which may partially explain the limitation of the phenotype associated with the V1951E, S196 L and P2083 L germline mutations to PA.
钙通道 3.2（Ca3.2）在神经兴奋性和醛固酮分泌中均发挥重要作用。最近的临床研究在 Ca3.2 通道中发现了四个种系突变（S196L、M1549I、V1951E 和 P2083L）。这四个突变均导致原发性醛固酮增多症（PA），而只有 M1549I 突变除了导致 PA 以外，还导致明显的神经功能障碍。在人类中，Ca3.2 通道基因（CACNA1H）有两个主要的剪接变异体，要么包含外显子 26，要么不包含。在这项研究中，我们检测了两种 CACNA1H 剪接变异体在人肾上腺皮质球状带细胞中的表达情况，以及 Ca3.2（-26）和 Ca3.2（+26）通道对四种 PA 突变是否具有不同的功能反应。我们发现人球状带细胞仅表达长形式的 Ca3.2（+26）通道。M1549I 突变使 Ca3.2（+26）通道的失活速度减缓了 5 倍以上，使 Ca3.2（-26）通道的失活速度减缓了 2 倍以上。S196L、V1951E 和 P2083L 突变使 Ca3.2（+26）通道从失活中恢复的速度加快，但对 Ca3.2（-26）通道没有影响。这四种突变均导致 Ca3.2（+26）通道的功能获得，导致醛固酮的过度产生。总之，四种 PA 突变对 Ca3.2（+26）电流的影响比对 Ca3.2（-26）电流的影响更为显著，除 M1549I 突变外，S196L、V1951E 和 P2083L 对 Ca3.2（-26）电流的电生理特性几乎没有影响，这可能部分解释了与 V1951E、S196L 和 P2083L 种系突变相关的表型局限性与 PA 相关的原因。
