In this study, Bax inhibitor-1 (BI-1release from ER microsomes from BI-1-overexpressing cells and BI-1-reconsituted liposomes. Acidic conditions also induced BI-1 protein oligomerization. Interestingly subjecting BI-1-overexpressing cells to acidic conditions induced more Bax recruitment to mitochondria, more cytochrome c release from mitochondria, and more cell death. These findings suggest that BI-1 increases Ca 2؉ leak rates from the ER through a mechanism that is dependent on pH and on the carboxyl-terminal cytosolic region of the BI-1 protein. The findings also reveal a cell death-promoting phenotype for BI-1 that is manifested under low pH conditions. The endoplasmic reticulum (ER)3 contains the largest calcium reserve in the cell (1, 2). Agonist-induced ER calcium release occurs through Ca 2ϩ channels such as inositol trisphosphate (IP 3 ) and ryanodine receptors (3). Calcium uptake into the ER occurs when the calcium release channels are closed (i.e. negative feedback to the IP 3 receptor) (4) and is performed by sarcoplasmic reticulum/ER-associated calcium-activated ATPase pumps (5). In the resting state, the Ca 2ϩ content of the ER reflects a balance between active uptake by sarcoplasmic reticulum/ER-associated calcium-activated ATPase and passive efflux or basal leakage through other Ca 2ϩ channels. This leakage is revealed when sarcoplasmic reticulum/ER-associated calcium-activated ATPase pumps are inhibited by agents such as thapsigargin (6), causing Ca 2ϩ to leak out of the ER into the cytosol.The Bax inhibitor-1 (BI-1) (also known as "testis enhanced gene transcript" (TEGT)) is an antiapoptotic protein capable of inhibiting Bax activation and translocation to mitochondria (7). This ubiquitously expressed protein contains several transmembrane domains and localizes to the ER. The homology of BI-1 sequences among species is striking, and the characteristic hydrophobicity and ER membrane localization are evolutionarily conserved (8). BI-1 affects calcium leakage from the ER as measured with Ca 2ϩ -sensitive, ER-targeted fluorescent proteins and Ca 2ϩ -sensitive dyes (9). However, the mechanism by which BI-1 regulates ER Ca 2ϩ fluxes remains unclear. Here we have provided additional evidence that BI-1 induces passive Ca 2ϩ leakage from the ER and also show that BI-1 activity is regulated by pH in a manner dependent on the carboxyl-terminal cytosolic domain of this protein.* This work was supported, in whole or in part, by National Institutes of Health Grant AG15393 (to J. C. R.). This work was also supported by Korea Research Foundation Grants KRF-2005-070-C00095, E00021, and 2005-015-E00210 and Korea Science and Engineering Foundation Grants R01-2006-000-10422-0 and R01-2007-000-20275-0. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Dendroaspis natriuretic peptide (DNP), a new member of the natriuretic peptide family, is structurally similar to atrial, brain, and C-type natriuretic peptides. However, the effects of DNP on the cardiac function are poorly defined. In the present study, we examined the effect of DNP on the cardiac L-type Ca2+ channels in rabbit ventricular myocytes. DNP inhibited the L-type Ca2+ current (ICa,L) in a concentration dependent manner with a IC50 of 25.5 nM, which was blocked by an inhibitor of protein kinase G (PKG), KT5823 (1 µM). DNP did not affect the voltage dependence of activation and inactivation of ICa,L. The α1c subunit of cardiac L-type Ca2+ channel proteins was phosphorylated by the treatment of DNP (1 µM), which was completely blocked by KT5823 (1 µM). Finally, DNP also caused the shortening of action potential duration in rabbit ventricular tissue by 22.3 ± 4.2% of the control (n = 6), which was completely blocked by KT5823 (1 µM). These results clearly indicate that DNP inhibits the L-type Ca2+ channel activity by phosphorylating the Ca2+ channel protein via PKG activation.

The present study was performed to investigate the potential effects of the unripened dried fruit of Rubus coreanus Miq., Rubi Fructus (RF), on hepatic steatosis and lipid metabolism in mice fed with a high-fat diet (HFD) known to induce obesity and hyperlipidaemia. Rubi Fructus extract (RFex) fed mice demonstrated a reduced body weight and adipose tissue weight. RFex fed mice also demonstrated decreased aminotransferase levels, lipid contents [triglyceride (TG), total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C)], leptin content and increased high‑density lipoprotein-cholesterol (HDL‑C) contents in the plasma. These effects were accompanied by a decreased expression of lipogenic genes, including sterol regulatory element binding protein-1c, liver X receptor, fatty acid synthase (FAS), acetyl‑CoA carboxylase, cluster of differentiation 36, lipoprotein lipase and decreased lipogenic enzyme FAS and 3-hydroxy-3 methylglutamyl coenzyme reductase enzyme activities, while elevating carnitine palmitoyltrasferase-1 activity. Based on these results, the present study hypothesized that the inhibitory effect on hepatic steatosis of RFex is the result of the suppression of lipid synthesis in mice fed with HFD, suggesting that RFex may be beneficial in preventing hepatic steatosis and liver lipotoxicity.

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