Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, H2X 0A9, Canada.
The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
Sci Rep. 2018 Jan 16;8(1):842. doi: 10.1038/s41598-018-19215-2.
Erythropoietin-producing human hepatocellular receptor (EPH) B6 (EPHB6) is a member of the receptor tyrosine kinase family. We previously demonstrated that EPHB6 knockout reduces catecholamine secretion in male but not female mice, and castration reverses this phenotype. We showed here that male EPHB6 knockout adrenal gland chromaffin cells presented reduced acetylcholine-triggered Ca influx. Such reduction depended on the non-genomic effect of testosterone. Increased large conductance calcium-activated potassium channel current densities were recorded in adrenal gland chromaffin cells from male EPHB6 knockout mice but not from castrated knockout or female knockout mice. Blocking of the large conductance calcium-activated potassium channel in adrenal gland chromaffin cells from male knockout mice corrected their reduced Ca influx. We conclude that the absence of EPHB6 and the presence of testosterone would lead to augmented large conductance calcium-activated potassium channel currents, which limit voltage-gated calcium channel opening in adrenal gland chromaffin cells. Consequently, acetylcholine-triggered Ca influx is reduced, leading to lower catecholamine release in adrenal gland chromaffin cells from male knockout mice. This explains the reduced resting-state blood catecholamine levels, and hence the blood pressure, in male but not female EPHB6 knock mice. These findings have certain clinical implications.
促红细胞生成素产生的人肝细胞受体 (EPH) B6 (EPHB6) 是受体酪氨酸激酶家族的一员。我们之前的研究表明，EPHB6 敲除会减少雄性而非雌性小鼠儿茶酚胺的分泌，而阉割可逆转这种表型。我们在这里表明，雄性 EPHB6 敲除肾上腺嗜铬细胞中乙酰胆碱触发的 Ca 内流减少。这种减少依赖于睾酮的非基因组效应。在雄性 EPHB6 敲除小鼠的肾上腺嗜铬细胞中记录到较大电导钙激活钾通道电流密度增加，但在去势敲除或雌性敲除小鼠中未记录到。在雄性敲除小鼠的肾上腺嗜铬细胞中阻断大电导钙激活钾通道可纠正其 Ca 内流减少。我们得出结论，EPHB6 的缺失和睾酮的存在会导致较大电导钙激活钾通道电流增加，从而限制肾上腺嗜铬细胞中电压门控钙通道的开放。因此，乙酰胆碱触发的 Ca 内流减少，导致雄性敲除小鼠的肾上腺嗜铬细胞中儿茶酚胺释放减少。这解释了雄性而非雌性 EPHB6 敲除小鼠的静息状态血液儿茶酚胺水平降低，从而导致血压降低。这些发现具有一定的临床意义。
