Bidirectional signaling by cell-adhesion molecules is thought to mediate synapse formation, but the mechanisms involved remain elusive. Here we found that the adhesion-G-protein-coupled receptors latrophilin-2 and latrophilin-3 selectively directed formation of perforant-path and Schaffer-collateral synapses, respectively, to hippocampal CA1-region neurons. Latrophilin-3 binds to two trans-cellular ligands, fibronectin leucine-rich-repeat transmembrane proteins (FLRTs) and teneurins. In vivo, both binding activities were required for input-specific synapse formation, suggesting that coincident binding of both ligands is necessary for synapse formation. In vitro, teneurin or FLRT alone did not induce excitatory synapse formation, whereas together they potently did so. Thus, postsynaptic latrophilins promote excitatory synapse formation by simultaneous binding of two unrelated presynaptic ligands, which is required for formation of synaptic inputs at specific dendritic localizations. INTRODUCTION: In brain, synaptic connections form neuronal communication networks, thereby constructing neural circuits. Synaptic connections are exquisitely specific and dynamic, but the underlying molecular mechanisms remain largely unexplored. In the hippocampus, Schaffer-collateral axons from the CA3 region form synapses on CA1 region pyramidal neurons exclusively on dendritic domains in the S. oriens and S. radiatum of these neurons. In contrast, perforant-path axons from the entorhinal cortex form synapses on CA1 region pyramidal neurons exclusively on dendritic domains in the S. lacunosum-moleculare. How this synaptic input specificity is achieved, however, and what signaling mechanisms maintain the two classes of synapses, is unknown. RATIONALE: Synapse formation is thought to involve bidirectional signaling by trans-synaptic cell-adhesion molecules. Building on recent observations that the adhesion G-protein coupled receptor (GPCR) latrophilin-2 is essential for synapses in the S. lacunosum-moleculare of the CA1 region, we asked whether distinct latrophilins are localized to different dendritic domains of CA1 region neurons. Moreover, latrophilins are known to form trans-cellular interactions with two classes of cell-adhesion molecules, teneurins and fibronectin leucine-rich-repeat transmembrane proteins (FLRTs). Thus we hypothesized that latrophilins may act in synapse formation via trans-synaptic interactions with these adhesion molecules as ligands, and that such interactions may contribute to the specificity of synapse formation. RESULTS: We produced genetic manipulations that allow monitoring the localization of endogenous latrophilin-2 and latrophilin-3 in vivo and that enable their conditional deletion. Using these manipulations, we found that latrophilin-2 and latrophilin-3 were specifically localized to postsynaptic spines in non-overlapping dendritic domains of CA1 region pyramidal neurons. Latrophilin-2 was targeted only to excitatory synapses in the S. lacunosum-moleculare, whereas latrophilin-3 was targeted o...
Ceramide is among a number of potential lipotoxic molecules that are thought to modulate cellular energy metabolism. The heart is one of the tissues thought to become dysfunctional due to excess lipid accumulation. Dilated lipotoxic cardiomyopathy, thought to be the result of diabetes and severe obesity, has been modeled in several genetically altered mice, including animals with cardiac-specific overexpression of glycosylphosphatidylinositol (GPI)-anchored human lipoprotein lipase (LpL GPI ). To test whether excess ceramide was implicated in cardiac lipotoxicity, de novo ceramide biosynthesis was inhibited pharmacologically by myriocin and genetically by heterozygous deletion of LCB1, a subunit of serine palmitoyltransferase (SPT). Inhibition of SPT, a rate-limiting enzyme in ceramide biosynthesis, reduced fatty acid and increased glucose oxidation in isolated perfused LpL GPI hearts, improved systolic function, and prolonged survival rates. Our results suggest a critical role for ceramide accumulation in the pathogenesis of lipotoxic cardiomyopathy.-Park, T
Increased secretion and levels of ApoB-containing lipoproteins (BLp) commonly occur in familial hyperlipidemia, obesity and diabetes. The plasma phospholipid-transfer protein (PLTP) is known to mediate transfer of phospholipids between BLp and HDL during their intravascular metabolism. To address a possible role of PLTP in dyslipidemia and atherogenesis, we bred mice deficient in the gene encoding PLTP (PLTP-deficient mice) using different hyperlipidemic mouse strains. In ApoB-transgenic and ApoE-deficient backgrounds, PLTP deficiency resulted in reduced production and levels of BLp and markedly decreased atherosclerosis. BLp secretion was diminished in hepatocytes from ApoB-transgenic PLTP-deficient mice, a defect that was corrected when PLTP was reintroduced in adenovirus. The studies reveal a major, unexpected role of PLTP in regulating the secretion of BLp and identify PLTP as a therapeutic target.
Abstract-Only a fraction of the clinical complications of atherosclerosis are explained by known risk factors. Animal studies have shown that plasma sphingomyelin (SM) levels are closely related to the development of atherosclerosis. SM carried into the arterial wall on atherogenic lipoproteins may be locally hydrolyzed by sphingomyelinase, promoting lipoprotein aggregation and macrophage foam cell formation. A novel, high-throughput, enzymatic method to measure plasma SM levels has been developed. Plasma SM levels were related to the presence of coronary artery disease (CAD) in a biethnic angiographic case-control study (279 cases and 277 controls). Plasma SM levels were higher in CAD patients than in control subjects (60Ϯ29 versus 49Ϯ21 mg/dL, respectively; PϽ0.0001). Moreover, the ratio of SM to SMϩphosphatidylcholine (PC) was also significantly higher in cases than in controls (0.33Ϯ0.13 versus 0.29Ϯ0.10, respectively; PϽ0.0001). Similar relationships were observed in African Americans and whites. Plasma SM levels showed a significant correlation with remnant cholesterol levels (rϭ0. 51, PϽ0.0001). By use of multivariate logistic regression analysis, plasma SM levels and the SM/(SMϩPC) ratio were found to have independent predictive value for CAD after adjusting for other risk factors, including remnants. The odds ratio (OR) for CAD was significantly higher for the third and fourth quartiles of plasma SM levels (OR T he association of lipid abnormalities and coronary atherosclerosis is well established. Case-control and prospective epidemiological studies have shown a direct correlation between coronary artery disease (CAD) and serum levels of total cholesterol and LDL cholesterol (LDL-C) and an inverse relationship between CAD and HDL cholesterol (HDL-C) levels. 1 However, compared with plasma cholesterol measurements, very little attention has been given to the relationship between phospholipids and CAD. 2,3 Atherogenesis is initiated by the interaction of cholesterol-rich lipoproteins, such as LDL, with the arterial wall. 4,5 The uptake of lipoprotein cholesterol by macrophages, leading to foam cell formation, is a central event in the initiation and progression of atherosclerosis. 6 However, native LDL is incapable of generating foam cells from macrophages. Thus, it is thought that LDL is modified in the arterial wall by processes such as oxidation, leading to macrophage chemotaxis and the uptake of modified LDL by macrophage foam cells. 7 Retention of lipoproteins on the subendothelial matrix, followed by aggregation, has also emerged as a central pathogenic process in macrophage foam cell formation and atherogenesis. 8 Lipoprotein aggregation in the vessel wall may result from enzymatic modification of LDL, induced by locally produced sphingomyelinase (SMase). 9 It has long been known that sphingomyelin (SM) accumulates in human and animal atheroma and that the major source is plasma lipoproteins. 10 Plasma SM levels are increased in human familial hyperlipidemias, especially in familial hypercholester...
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