The heart has a dynamic compensatory mechanism for haemodynamic stress. However, the molecular details of how mechanical forces are transduced in the heart are unclear. Here we show that the transient receptor potential, vanilloid family type 2 (TRPV2) cation channel is critical for the maintenance of cardiac structure and function. Within 4 days of eliminating TRPV2 from hearts of the adult mice, cardiac function declines severely, with disorganization of the intercalated discs that support mechanical coupling with neighbouring myocytes and myocardial conduction defects. After 9 days, cell shortening and Ca2+ handling by single myocytes are impaired in TRPV2-deficient hearts. TRPV2-deficient neonatal cardiomyocytes form no intercalated discs and show no extracellular Ca2+-dependent intracellular Ca2+ increase and insulin-like growth factor (IGF-1) secretion in response to stretch stimulation. We further demonstrate that IGF-1 receptor/PI3K/Akt pathway signalling is significantly downregulated in TRPV2-deficient hearts, and that IGF-1 administration partially prevents chamber dilation and impairment in cardiac pump function in these hearts. Our results improve our understanding of the molecular processes underlying the maintenance of cardiac structure and function.
Background:The biosynthetic pathway for the ligand-binding moiety of ␣-dystroglycan, defects in which cause dystroglycanopathy, remains unclear.
Results:The phosphodiester-linked moiety on O-mannose is absent in dystroglycanopathy models and in wild-type lung and testis. Conclusion: Post-phosphoryl modification is a key determinant of the functional expression of ␣-dystroglycan as a laminin receptor. Significance: This work expands our understanding of the molecular mechanism of a unique post-translational modification.
BackgroundcAMP-dependent protein kinase (PKA) has been implicated in the asexual stage of the Toxoplasma gondii life cycle through assaying the effect of a PKA-specific inhibitor on its growth rate. Since inhibition of the host cell PKA cannot be ruled out, a more precise evaluation of the role of PKA, as well as characterization of the kinase itself, is necessary.Methodology/Principal FindingThe inhibitory effects of two PKA inhibitors, H89, an ATP-competitive chemical inhibitor, and PKI, a substrate-competitive mammalian natural peptide inhibitor, were estimated. In the in vitro kinase assay, the inhibitory effect of PKI on a recombinant T. gondii PKA catalytic subunit (TgPKA-C) was weaker compared to that on mammalian PKA-C. In a tachyzoite growth assay, PKI had little effect on the growth of tachyzoites, whereas H89 strongly inhibited it. Moreover, T. gondii PKA regulatory subunit (TgPKA-R)-overexpressing tachyzoites showed a significant growth defect.Conclusions/SignificanceOur data suggest that PKA plays an important role in the growth of tachyzoites, and the inhibitory effect of substrate-competitive inhibitor PKI on T. gondii PKA was low compared to that of the ATP competitive inhibitor H89.
A chiral amino alcohol,
cis-2-amino-3,3-dimethyl-1-indanol (2), was
converted into the corresponding
enantiomerically pure phosphorus-containing oxazoline 4.
Oxazoline 4 was found to be an efficient
ligand for palladium-catalyzed enantioselective allylic amination
reactions: In the amination
reaction of (E)-1,3-diphenyl-2-propen-1-yl acetate
(7a), 4 was found to be more efficient than
the
similar ligands 1a−c, derived from valinol,
tert-leucinol, etc. Other
1,3-bis(p-substituted aryl)-2-propen-1-yl acetates were also converted to the corresponding amines in
a similar manner and
with excellent enantioselectivity. In the amination reaction of
1-alkyl-3,3-diphenyl-2-propen-1-yl
acetates 11, the correponding amines 12 were
obtained with excellent enantioselectivity when acetic
acid was added to the reaction system.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.