The preceding results show no association

The preceding results show no association between the EP1 gene polymorphisms and suicide completers in the Japanese population. Impulsive aggression is one of the most important risk factors for suicide especially in the younger generation (Brent et al., 2002, Melhem et al., 2007). EP1 knockout mice displayed impulsive and aggressive behaviors under social or environmental stresses (Matsuoka et al., 2005). In addition, PGE2 action on the EP1 receptor has been reported to be age related (Wu and Meydani, 2004, Wu and Meydani, 2008). Therefore, it is interesting to analyze the data for the younger subjects. Although our sample size for the younger subjects (≤35years) was too small to conclude, significant association between the promoter SNPs and female young suicide completers was observed (Supplementary Table 1). Because the rate of suicide is 3.5 times higher in males than females (World Health Organization, 2005), it is very likely that the mechanisms involved in the pathogenesis of suicide are different between males and females. Animal studies revealed that PGE2 signaling is involved in brain gender differentiation and subsequent disruption might cause behavioral abnormalities later in life (Ottem et al., 2004). EP1 expression is also related to hormonal status in females, and EP1 signaling might induce different actions in males and females (Stock et al., 2000; Stapleton et al., 2004). In our study, the MAFs of the female suicide completers were lower than the female controls in all analyses resulting in nominal significant difference. This result suggested that these polymorphisms might have protective role in the female toward suicidal behaviors which might be mediated by the EP1 signaling effect on gender differentiation. Nevertheless, it would be interesting to further study the EP1 signaling to characterize the behavior of the female knock out animal in comparison to its male counterpart. The following are the supplementary materials related to this article.
Acknowledgment This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan.
Prostanoids are a family of oxidative metabolites of arachidonic 6206 that act in a autocrine and paracrine fashion. The cyclooxygenase activity of COX-1 and COX-2 converts arachidonic acid to prostaglandin G (PGG) and the peroxidase activity of the same enzymes reduces PGG to prostaglandin H (PGH). PGH is then isomerized to the five principal prostanoids by their respective synthases. Prostanoids bind to and activate a family of cell surface G-protein coupled receptors. Prostaglandin E (PGE) is formed from PGH by prostaglandin E synthases (cPGES, mPGES-1, mPGES-2) and is a major prostanoid produced by the kidney and the vasculature. The bioactivity of PGE is mediated through four subtypes of E-Prostanoid (EP) receptors, designated EP1-EP4. EP2 and EP4 couple to stimulatory G-proteins, which increase intracellular cAMP when activated. EP3 canonically couples to inhibitory G-proteins, suppressing cAMP accumulation. Both EP1 and EP3 are known to induce calcium flux into the cell., The tissue localization of each of these EP receptors produces diverse and sometimes opposing biological activities of PGE in vivo. Hypertension and diabetes are the primary causes of 62% of patients with end-stage renal disease (ESRD) and 72% of patients that develop ESRD each year, which requires life-long dialysis or kidney transplantation for survival. Elimination of PGE production with COX inhibitors,, like NSAIDs, is not a viable option as highlighted in a number of clinical trials. Recent studies in rodents and humans have suggested a role for the EP1 receptor in mediating at least part of the pathophysiology of diabetes mellitus, , and hypertension., , , EP1 has been prosecuted as a potential therapeutic target for chronic pain., , , , As such, small molecule, drug-like antagonists of EP1 have been developed. Human prostanoid receptor-targeting molecules are often nonselective, owing to the evolution of the EP family of GPCRs to recognize the same endogenous ligand, PGE. The molecular pharmacology of these compounds at mouse prostanoid receptors is less well known, often poorly selective, and not always comparable to human pharmacology. In order to study these molecular targets more precisely, we developed EP1 antagonists selective for the mouse receptor to use in mouse models of hypertension and diabetes mellitus.