Mechanisms of PiT2-loop7 Missense Mutations Induced Pi Dyshomeostasis / 神经科学通报·英文版

PiT2 is an inorganic phosphate (Pi) transporter whose mutations are linked to primary familial brain calcification (PFBC). PiT2 mainly consists of two ProDom (PD) domains and a large intracellular loop region (loop7). The PD domains are crucial for the Pi transport, but the role of PiT2-loop7 remains unclear. In PFBC patients, mutations in PiT2-loop7 are mainly nonsense or frameshift mutations that probably cause PFBC due to C-PD1131 deletion. To date, six missense mutations have been identified in PiT2-loop7; however, the mechanisms by which these mutations cause PFBC are poorly understood. Here, we found that the p.T390A and p.S434W mutations in PiT2-loop7 decreased the Pi transport activity and cell surface levels of PiT2. Furthermore, we showed that these two mutations attenuated its membrane localization by affecting adenosine monophosphate-activated protein kinase (AMPK)- or protein kinase B (AKT)-mediated PiT2 phosphorylation. In contrast, the p.S121C and p.S601W mutations in the PD domains did not affect PiT2 phosphorylation but rather impaired its substrate-binding abilities. These results suggested that missense mutations in PiT2-loop7 can cause Pi dyshomeostasis by affecting the phosphorylation-regulated cell-surface localization of PiT2. This study helps understand the pathogenesis of PFBC caused by PiT2-loop7 missense mutations and indicates that increasing the phosphorylation levels of PiT2-loop7 could be a promising strategy for developing PFBC therapies.

Gαq-RGS2 loop activator modulates the activity of vario us agonists on isolated heart and aorta of normal rats

The Gαq-RGS2 loop activator, 1-(5-chloro-2-hydroxyphenyl)-3-(4-(trifluoromethyl)-phenyl)-1H-1,2,4-triazol-5(4H)-one has demonstrated Gαq signaling inhibitor activity. Therefore, we aimed to study the effect of Gαq-RGS2 loop activator on isolated heart and aorta of normal rats. Heart and aorta were isolated from the sacrificed rats (n=6) and mounted on the langendroff's and organ bath assembly, respectively. The effect of various receptor-dependent (acetylcholine, angiotensin II and adrenaline) and independent (calcium chloride and sodium nitroprusside) agonists in absence and presence of Gαq-RGS2 loop activator on left ventricular systolic pressure (LVSP) and the contractile responseswere evaluated in isolated heart and aorta, respectively. Gαq-RGS2 loop activator (100 µM) significantly attenuated the adrenaline (p<0.001,) and angiotensin II (p<0.001) induced increase in LVSP in isolated heart and contractile response of adrenaline (p<0.01) and angiotensin II (p<0.01) in the aorta. However, effect calcium chloride did not significantly alter by Gαq-RGS2 loop activator. The effect of acetylcholinewas significantly (p<0.01, p<0.05) increased by Gαq-RGS2 loop activator in isolated heart and aorta. The effect of sodium nitroprusside significantly (p<0.01) potentiated by Gαq-RGS2 loop activator (100 µM) in isolated heart while it did not significantly alters in the aorta. Ultimately, the Gαq-RGS2 loop activator modulated the action of receptor-dependent agonists in isolated heart and aorta

2-loop En Block Double Fold Operation through 3 Small Incision

Korean small eyes are characterized in thickness and pseudoptosis of the skin of the upper eyelid. They also have a large amount of subcutaneous and preaponeurotic fat. The hypertrophic orbicularis oculi muscles and the lower positioned transverse ligaments are included in their structural characteristics. These special features act as various burden factors in Korean double eyelid operation. Just burden factors restrict the movement of the upper eyelid and so Korean eyes looks like Ptosis (pseudoptosis). For creation of double fold eyelid, we performed continuous 2-loop single stitch buried suture to make an en bloc fixation with dermis, levator aponeurosis and Muller muscle through three small incisions. And then we tried to eliminate the burden factors through small sized lateral incision. After removal of the external sutures at postoperative 3 days, we obtained our intended double fold lines such as in-fold, in-ward fold and out fold successfully and only experienced minor complications such as edema, ecchymosis and loss of fold. And also the range of excursion in the upper eyelid improved without levator shortening or any other operation such as a sling. The objective of this article is to share our experience and to introduce our method of treating Korean pseudoptotic eyes by using 2-loop en bloc fixation through three small incisions with various reviews of literature.