Komiyama Tomoyoshi, Hirokawa Takatsugu, Sato Kyoko, Oka Akira, Kamiguchi Hiroshi, Nagata Eiichiro, Sakura Hiroshi, Otsuka Kuniaki, Kobayashi Hiroyuki
Department of Clinical Pharmacology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
The National Institute of Advanced Industrial Science and Technology (AIST), Tokyo Waterfront Bio-IT Research Building 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan.
PLoS One. 2015 Apr 10;10(4):e0120788. doi: 10.1371/journal.pone.0120788. eCollection 2015.
The objective of this study was to clarify the effects of disease on neurally mediated syncope (NMS) during an acute stress reaction. We analyzed the mechanism of the molecular interaction and the polymorphisms of the alpha-2 adrenoreceptor (α2B-AR) gene as the potential psychiatric cause of incentive stress. We focused on the following three genotypes of the repeat polymorphism site at Glu 301-303 in the α2B-AR gene: Glu12/12, Glu12/9, and Glu9/9. On the basis of our clinical research, NMS is likely to occur in people with the Glu12/9 heterotype. To verify this, we assessed this relationship with the interaction of Gi protein and adenylate cyclase by in silico analysis of the Glu12/9 heterotype. By measuring the difference in the dissociation time of the Gi-α subunit twice, we found that the Glu12/9 heterotype suppressed the action of adenylate cyclase longer than the Glu homotypes. As this difference in the Glu repeat number effect is thought to be one of the causes of NMS, we investigated the evolutionary significance of the Glu repeat number. Glu8 was originally repeated in simians, while the Glu12 repeats occurred over time during the evolution of bipedalism in humans. Taken with the Glu12 numbers, NMS would likely become a defensive measure to prevent significant blood flow to the human brain.
本研究的目的是阐明疾病在急性应激反应期间对神经介导性晕厥（NMS）的影响。我们分析了分子相互作用机制以及α2肾上腺素能受体（α2B-AR）基因的多态性，将其作为诱发应激的潜在精神原因。我们重点关注α2B-AR基因中Glu 301-303重复多态性位点的以下三种基因型：Glu12/12、Glu12/9和Glu9/9。基于我们的临床研究，NMS可能发生在具有Glu12/9异型的人群中。为了验证这一点，我们通过对Glu12/9异型进行计算机模拟分析，评估了其与Gi蛋白和腺苷酸环化酶相互作用的关系。通过两次测量Gi-α亚基解离时间的差异，我们发现Glu12/9异型比Glu同型对腺苷酸环化酶作用的抑制时间更长。由于Glu重复数效应的这种差异被认为是NMS的原因之一，我们研究了Glu重复数的进化意义。Glu8最初在猿猴中重复出现，而Glu12重复则是在人类两足动物进化过程中随着时间出现的。结合Glu12的数量来看，NMS可能会成为一种防止大量血液流向人类大脑的防御机制。
