However, many GPCRs, when activated or blocked by drugs, elicit both beneficial and adverse pharmacology. Recent work has Protein Tyrosine Kinase inhibitor demonstrated that in some cases, the salutary and deleterious signals linked to a specific GPCR can be selectively targeted by “”biased ligands”" that entrain subsets of a receptor’s normal pharmacology. This review briefly summarizes the advances and current state of the biased ligand field, focusing on an example: biased ligands targeting the angiotensin II type 1 receptor. These compounds exhibit unique pharmacology, distinct from classic agonists or antagonists, and one such molecule is now in clinical development for the treatment of acute heart failure.

(C) 2013 Elsevier Inc. All rights reserved.”
“Spinal muscular atrophy (SMA), a fatal genetic motor disorder of infants, is caused by diminished full-length survival of motor neuron (SMN) protein levels. Normally involved in small nuclear ribonucleoprotein (snRNP) assembly and pre-mRNA splicing, recent studies suggest that SMN plays a critical role in regulating apoptosis. Interestingly, the anti-apoptotic Bcl-x isoform, Bcl-xL, is reduced in SMA. In a related finding, Sam68, an RNA-binding protein, was found to modulate splicing of SMN and Bcl-xL transcripts, PCI-32765 chemical structure promoting SMN Delta 7 and pro-apoptotic Bcl-xS transcripts. Here we demonstrate that Bcl-xL expression

increases SMN protein by similar to 2-fold in SH-SY5Y cells. Conversely, SMN expression increases Bcl-xL protein levels by similar to 6-fold in SH-SY5Y cells, and similar to 2.5-fold in the brains of transgenic mice over-expressing SMN (PrP-SMN). Moreover, Sam68 protein levels were markedly reduced following SMN and Bcl-xL expression in SH-SY5Y cells, suggesting a feedback mechanism co-regulating levels of both proteins. We also found that exogenous SMN expression increased full-length SMN transcripts, possibly by promoting exon 7 inclusion. Finally, co-expression

of SMN and Bcl-xL triclocarban produced an additive anti-apoptotic effect following PI3-kinase inhibition in SH-SY5Y cells. Our findings implicate Bcl-xL as another potential target in SMA therapeutics, and indicate that therapeutic increases in SMN may arise from modest increases in total SMN. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.”
“In order to investigate the unique contribution of individual wine grape (Vitis vinifera) berry tissues and water-deficit to wine quality traits, a survey of tissue-specific differences in protein and selected metabolites was conducted using pericarp (skin and pulp) and seeds of berries from vines grown under well-watered and water-deficit stress conditions. Of 1047 proteins surveyed from pericarp by 2-D PAGE, 90 identified proteins showed differential expression between the skin and pulp.