Relationship between human evolution and neurally mediated syncope disclosed by the polymorphic sites of the adrenergic receptor gene α2B-AR

Abstract

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.

Fig 1. Phylogenetic tree constructed by the neighbor-joining method showing the complete mitochondrial DNA (mtDNA) region (16,750 bp) of Homo sapiens sapiens and Homo sapiens neanderthalensis and suggesting the evolution of the Glu12 repeats.

On the basis of the differences in Glu12 frequency in the three groups, it is likely that most ancestors of modern-day Africans primarily had Glu12 repeats of the α2B-AR gene, and not Glu9 repeats.

Fig 2. Phylogenetic tree constructed by the unweighted pair group method method showing the complete mtDNA region (16,750 bp) of 3 Homo sapiens sapiens and 6 primates and suggesting the evolution of the Glu9 and Glu12 repeats in the α2B-AR gene.

The variability of the Glu repeats increased during the evolution of early primates to humans. This development likely changed the role of vasoconstriction in blood pressure while in an upright position.

Fig 3. Helix wheel (a) and binding site of Glu9 (b) and Glu12 (c).

The helix wheel is mostly unchanged functionally as Glu9 and Glu12 bind to the site in the adjoining position.

Fig 4. Binding energy of Gi α-subunit protein by in silico analysis.

The receptor included in the Glu12 repeats can be released quickly from the β and γ subunits. The α subunit has a faster effect on adenylate cyclase signaling.