The Low Density Lipoprotein Receptor Gene Family

Stockinger, Walter; Hengstschläger-Ottnad, Elke; Novak, Sabine; Matus, Andrew; Hüttinger, Manfred; Bauer, Jan; Lassmann, Hans; Schneider, Wolfgang J.; Nimpf, Johannes

doi:10.1074/jbc.273.48.32213

Cited by 69 publications

(26 citation statements)

References 44 publications

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“…The results of the current study might suggest that MUG I is transported to neurons through the blood-brain barrier. On the other hand, the localization of MUG I was consistent with the localization of LRP described previously (67,68). Additionally, since r-actNP only formed an SDS-stable complex with MUG I, endogenous actNP might interact with MUG I after degrading components of the ECM, and then the binding of MUG I to LRP might lead to endocytosis and degradation of NP (32).…”

Section: Discussionsupporting

confidence: 62%

Serine Proteinase Inhibitor 3 and Murinoglobulin I Are Potent Inhibitors of Neuropsin in Adult Mouse Brain

Kato

Kishi

Kamachi

et al. 2001

Journal of Biological Chemistry

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Extracellular serine protease neuropsin (NP) is expressed in the forebrain limbic area of adult brain and is implicated in synaptic plasticity. We screened for endogenous NP inhibitors with recombinant NP (r-NP) from extracts of the hippocampus and the cerebral cortex in adult mouse brain. Two SDS-stable complexes were detected, and after their purification, peptide sequences were determined by amino acid sequencing and mass spectrometry, revealing that target molecules were serine proteinase inhibitor-3 (SPI3) and murinoglobulin I (MUG I). The addition of the recombinant SPI3 to r-NP resulted in an SDS-stable complex, and the complex formation followed bimolecular kinetics with an association rate constant of 3.4 ؎ 0.22 ؋ 10 6 M ؊1 s ؊1, showing that SPI3 was a slow, tight binding inhibitor of NP. In situ hybridization histochemistry showed that SPI3 mRNA was expressed in pyramidal neurons in the hippocampal CA1-CA3 subfields, as was NP mRNA. Alternatively, the addition of purified plasma MUG I to r-NP resulted in an SDS-stable complex, and MUG I inhibited degradation of fibronectin by r-NP to 24% at a r-NP/MUG I molar ratio of 1:2. Immunofluorescence histochemistry showed that MUG I localized in the hippocampal neurons. These findings indicate that SPI3 and MUG I serve to inactivate NP and control the level of NP in adult brain, respectively. Extracellular proteolysis exerted by secretory serine proteases has been implicated in neural development, plasticity, and degeneration and regeneration in the nervous system (1) and might be controlled by specific inhibitors (2). Neuropsin (NP), 1 a serine protease with a chimeric structure similar to trypsin and nerve growth factor-␥ (3), was found to be expressed in the nervous system (4) and has been demonstrated to be engaged in activity-dependent plasticity changes in neurons. NP mRNA and protein levels increased in the hippocampus after kindled seizures and injection of antibody against NP led to retardation of epilepticus in mice (5, 6). Furthermore, application of recombinant NP induced an increase in the amplitude of the tetanic stimulation-induced early phase long term potentiation in the Schaffer collateral pathway (7). It has been proposed that the plasticity changes are regulated by the balance between the accumulation and degradation of the extracellular matrix (ECM) proteins. There is, indeed, some evidence that the formation of hippocampal LTP is attributable to cell-ECM interactions, involving cadherin (8), integrin (9, 10), N-syndecan (11), cell adhesion molecules, NCAM, and L1 (12)(13)(14). NP acted to degrade ECM including fibronectin (15), for which integrins were receptors (16, 17), and L1. 2 Therefore, rearrangement of these ECM components by NP and a specific inhibitor might implicated in the formation of LTP.As another characteristic of NP, it has been shown that NP mRNA was restricted to neurons in the limbic areas of adult brain involving the CA1-CA3 subfields of the hippocampus, the amygdaloid nucleus, the cingulate cortex, the anterior olfact...

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Section: Discussionsupporting

confidence: 62%

Serine Proteinase Inhibitor 3 and Murinoglobulin I Are Potent Inhibitors of Neuropsin in Adult Mouse Brain

Kato

Kishi

Kamachi

et al. 2001

Journal of Biological Chemistry

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“…apoER2͞ VLDL-r double-null animals develop a reeler phenotype (30), and because reelin is a ligand for apoER2 and VLDL-r, this supports the idea that these receptors directly mediate reelin signal transduction (30,31). It is interesting to note that both VLDL-r and apoER2 also are expressed strongly on mature neurons (32,33), and apoER2 has been reported to be an ␣ 2 M* receptor (10). Our data with a specific anti-LRP antibody clearly implicate LRP itself but do not rule out a role for apoER2 in calcium signaling.…”

Section: Discussionsupporting

confidence: 48%

“…Treatment with methylamine leads to the same conformational change and is used experimentally to generate ␣ 2 M* (9). LRP (3) and apoER2 (10) are the only known brain receptors for ␣ 2 M*, mediating clearance of protease͞protease inhibitor complexes.…”

mentioning

confidence: 99%

The endocytic receptor protein LRP also mediates neuronal calcium signaling via N -methyl- d -aspartate receptors

Bacskai

Xia

Strickland

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

178

155

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The low density lipoprotein receptor-related protein (LRP) is an endocytic receptor that is a member of the low density lipoprotein receptor family. We report that the LRP ligand, activated ␣2-macroglobulin (␣ 2M*), induces robust calcium influx in cultured primary neurons, but not in nonneuronal LRP-containing cells in the same culture. The calcium influx is mediated through N-methyl-D-aspartate receptor channels, which explains the neuron specificity of the response. Microapplication of ␣2M* leads to a localized response at the site of application that dissipates rapidly, suggesting that the calcium signal is temporally and spatially discrete. Calcium influx to ␣2M* is blocked by the physiological LRP inhibitor, receptor-associated protein. Bivalent antibodies to the extracellular domain of LRP, but not Fab fragments of the same antibody, cause calcium influx, indicating that the response is specific to LRP and may require dimerization of the receptor. Thus, LRP is an endocytic receptor with a novel signaling role. T he low density lipoprotein (LDL) receptor is one of the best studied examples of an endocytic receptor, delivering cholesterol-containing lipoproteins and other ligands to acidic compartments within cells for further metabolism. A family of homologous receptors plays similar roles in various tissues, including the very low density lipoprotein receptor (VLDL-r), the apolipoprotein E receptor 2 (apoER2), the LDL receptorrelated protein (LRP), and megalin (or GP330). We now report a neuron-specific signaling role for LRP: ligand binding and receptor dimerization lead to calcium influx via N-methyl-Daspartate receptor (NMDAR) channels.LRP is a widely expressed endocytic receptor that is strongly expressed in brain on neurons and reactive astrocytes (1). LRP is a Ͼ600-kDa (4,454-aa) protein cleaved in the trans-Golgi network to form a heterodimer with a single transmembranespanning domain, a Ϸ515-kDa extracellular region containing four ligand-binding repeat regions, multiple epidermal growth factor and other growth factor repeats, and a smaller intracellular domain containing two NPXY sequences that direct endocytosis of the receptor to clathrin-coated pits (2-4). LRP has more than 15 identified ligands that fall into several broad categories: proteinase͞proteinase inhibitor complexes including activated ␣ 2 -macroglobulin (␣ 2 M*), apoE and lipid-related ligands, and others such as lactoferrin. The 39-kDa receptorassociated protein (RAP) is an endoplasmic chaperone protein tightly bound to LRP, which, when used pharmacologically, specifically blocks and prevents uptake of all known LRP ligands (3,5,6). Like other members of the LDL receptor family, LRP binds and imports these ligands into intracellular vesicles, where the ligand is released and the receptor is recycled to the surface.␣ 2 M is a unique pan-protease inhibitor that is synthesized and secreted in the brain (7). A tetrameric complex undergoes a conformational alteration when a ''bait'' region is cleaved by a protease. This both sterically...

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“…The LDL-receptor Contributes to LPL-mediated Holoparticle Binding and Turnover-The fact that BCECs express the LDLreceptor (32)(33)(34) prompted us to study the interaction of the LDL-receptor and LPL at the BBB. During these experiments ( To exclude the possibility that the effects described in Fig.…”

Section: Resultsmentioning

confidence: 99%

Effects of Lipoprotein Lipase on Uptake and Transcytosis of Low Density Lipoprotein (LDL) and LDL-associated α-Tocopherol in a Porcine in Vitro Blood-Brain Barrier Model

Goti¹,

Balázs²,

Panzenboeck³

et al. 2002

Journal of Biological Chemistry

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During the present study the contribution of lipoprotein lipase (LPL) to low density lipoprotein (LDL) holoparticle and LDL-lipid (␣-tocopherol (␣TocH)) turnover in primary porcine brain capillary endothelial cells (BCECs) was investigated. The addition of increasing LPL concentrations to BCECs resulted in up to 11-fold higher LDL holoparticle cell association. LPL contributed to LDL holoparticle turnover, an effect that was substantially increased in response to LDL-receptor upregulation. The addition of LPL increased selective uptake of LDL-associated ␣TocH in BCECs up to 5-fold. LPL-dependent selective ␣TocH uptake was unaffected by the lipase inhibitor tetrahydrolipstatin but was substantially inhibited in cells where proteoglycan sulfation was inhibited by treatment with NaClO 3 . Thus, selective uptake of LDL-associated ␣TocH requires interaction of LPL with heparan-sulfate proteoglycans. Although high level adenoviral overexpression of scavenger receptor BI (SR-BI) in BCECs resulted in a 2-fold increase of selective LDL-␣TocH uptake, SR-BI did not act in a cooperative manner with LPL. Although the addition of LPL to BCEC Transwell cultures significantly increased LDL holoparticle cell association and selective uptake of LDL-associated ␣TocH, holoparticle transcytosis across this porcine blood-brain barrier (BBB) model was unaffected by the presence of LPL. An important observation during transcytosis experiments was a substantial ␣TocH depletion of LDL particles that were resecreted into the basolateral compartment. The relevance of LPL-dependent ␣TocH uptake across the BBB was confirmed in LPL-deficient mice. The absence of LPL resulted in significantly lower cerebral ␣TocH concentrations than observed in control animals.

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The Low Density Lipoprotein Receptor Gene Family

Cited by 69 publications

References 44 publications

Serine Proteinase Inhibitor 3 and Murinoglobulin I Are Potent Inhibitors of Neuropsin in Adult Mouse Brain

Serine Proteinase Inhibitor 3 and Murinoglobulin I Are Potent Inhibitors of Neuropsin in Adult Mouse Brain

The endocytic receptor protein LRP also mediates neuronal calcium signaling via N -methyl- d -aspartate receptors

Effects of Lipoprotein Lipase on Uptake and Transcytosis of Low Density Lipoprotein (LDL) and LDL-associated α-Tocopherol in a Porcine in Vitro Blood-Brain Barrier Model

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