The N-Terminal Extracellular Domain 23−60 of the Calcitonin Receptor-Like Receptor in Chimeras with the Parathyroid Hormone Receptor Mediates Association with Receptor Activity-Modifying Protein 1

Ittner, Lars M.; Koller, Daniela; Muff, Roman; Fischer, Jan A.; Born, Walter

doi:10.1021/bi048111o

Cited by 45 publications

(32 citation statements)

References 18 publications

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“…Proteins were extracted according to solubility as described, using FA or sarkosyl (49,50). Western blotting was performed as described (51). Primary antibodies were to human tau (HT7), tau phosphorylated at S422 (pS422; Invitrogen), S262/S356 (12E8; P. Seubert, Elan Pharmaceuticals, San Francisco, CA), S396/S404 (PHF-1; P. Davies, Albert Einstein College of Medicine, New York, NY), S202/T205 (AT8) and T181 (AT270; Thermo), PP2A subunit C (PP2AC; Millipore), Gapdh and actin (both Chemicon), and HA tag (Roche).…”

Section: Neuroscience Methodsmentioning

confidence: 99%

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Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models

Eersel

Liu

et al. 2010

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

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247

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Alzheimer's disease (AD) brains are characterized by amyloid-β-containing plaques and hyperphosphorylated tau-containing neurofibrillary tangles (NFTs); however, in frontotemporal dementia, the tau pathology manifests in the absence of overt amyloid-β plaques. Therapeutic strategies so far have primarily been targeting amyloid-β, although those targeting tau are only slowly beginning to emerge. Here, we identify sodium selenate as a compound that reduces tau phosphorylation both in vitro and in vivo. Importantly, chronic oral treatment of two independent tau transgenic mouse strains with NFT pathology, P301L mutant pR5 and K369I mutant K3 mice, reduces tau hyperphosphorylation and completely abrogates NFT formation. Furthermore, treatment improves contextual memory and motor performance, and prevents neurodegeneration. As hyperphosphorylation of tau precedes NFT formation, the effect of selenate on tau phosphorylation was assessed in more detail, a process regulated by both kinases and phosphatases. A major phosphatase implicated in tau dephosphorylation is the serine/threonine-specific protein phosphatase 2A (PP2A) that is reduced in both levels and activity in the AD brain. We found that selenate stabilizes PP2A-tau complexes. Moreover, there was an absence of therapeutic effects in sodium selenate-treated tau transgenic mice that coexpress a dominant-negative mutant form of PP2A, suggesting a mediating role for PP2A. Taken together, sodium selenate mitigates tau pathology in several AD models, making it a promising lead compound for tau-targeted treatments of AD and related dementias.

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Section: Neuroscience Methodsmentioning

confidence: 99%

“…Fixed cells were stained as previously described (51). Primary antibodies pS422 and HT7 were visualized with Alexa-coupled secondary antibodies.…”

Section: Neuroscience Methodsmentioning

confidence: 99%

Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models

Eersel

Liu

et al. 2010

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

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247

204

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“…Immunoprecipitation (IP) was performed as described previously (36). Briefly, tissue was lysed with a glass Dounce homogenizer in buffer containing 20 mM Tris-HCl, pH 7.5, 150 mM sodium chloride, 1% Triton X-100 (Sigma) and Complete Protease inhibitor (Roche Applied Science).…”

Section: Methodsmentioning

confidence: 99%

“…COS7 cells maintained in Dulbecco's modified Eagle's medium/F-12 containing 10% fetal bovine serum (Hyclone) and transfected as previously described (36). Cells were incubated with okadaic acid (OA) in culture medium for 10 h at 37°C, 5%CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Phosphorylated Tau Interacts with c-Jun N-terminal Kinase-interacting Protein 1 (JIP1) in Alzheimer Disease

Ittner

Götz

2009

Journal of Biological Chemistry

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137

103

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In Alzheimer disease (AD) and frontotemporal dementia the microtubule-associated protein Tau becomes progressively hyperphosphorylated, eventually forming aggregates. However, how Tau dysfunction is associated with functional impairment is only partly understood, especially at early stages when Tau is mislocalized but has not yet formed aggregates. Impaired axonal transport has been proposed as a potential pathomechanism, based on cellular Tau models and Tau transgenic mice. We recently reported K369I mutant Tau transgenic K3 mice with axonal transport defects that suggested a cargo-selective impairment of kinesin-driven anterograde transport by Tau. Here, we show that kinesin motor complex formation is disturbed in the K3 mice. We show that under pathological conditions hyperphosphorylated Tau interacts with c-Jun N-terminal kinase-interacting protein 1 (JIP1), which is associated with the kinesin motor protein complex. As a result, transport of JIP1 into the axon is impaired, causing JIP1 to accumulate in the cell body. Because we found trapping of JIP1 and a pathological Tau/ JIP1 interaction also in AD brain, this may have pathomechanistic implications in diseases with a Tau pathology. This is supported by JIP1 sequestration in the cell body of Tau-transfected primary neuronal cultures. The pathological Tau/JIP1 interaction requires phosphorylation of Tau, and Tau competes with the physiological binding of JIP1 to kinesin light chain. Because JIP1 is involved in regulating cargo binding to kinesin motors, our findings may, at least in part, explain how hyperphosphorylated Tau mediates impaired axonal transport in AD and frontotemporal dementia.

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“…Like family B receptors, single transmembrane domain RAMPs contain a large extracellular domain that is structured by conserved disulfide bridges. In the best studied case of RAMP-receptor interaction, that of the calcitonin-like receptor with RAMP1, both the aminoterminal extracellular domain and transmembrane domain of RAMP1 contribute to the interface, and indeed weak, but functional dimerization can occur via the amino-terminal domain alone (Fitzsimmons et al, 2003;Ittner et al, 2005). It is possible, therefore, that an analogous situation occurs in the formation of receptor homo-and hetero-dimers, although this remains to be empirically determined.…”

Section: Vpac and Secretin Receptor Oligomerization 369mentioning

confidence: 99%

Constitutive Formation of Oligomeric Complexes between Family B G Protein-Coupled Vasoactive Intestinal Polypeptide and Secretin Receptors

et al. 2005

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Formation of oligomeric complexes of family A G protein-coupled receptors has been shown to influence their function and regulation. However, little is known about the existence of such complexes for family B receptors in this superfamily. We previously used bioluminescence resonance energy transfer (BRET) to demonstrate that the prototypic family B secretin receptor forms ligand-independent oligomeric complexes. Here, we show that subtypes of human vasoactive intestinal polypeptide receptors (VPAC1 and VPAC2) that represent the closest structurally related receptors to the secretin receptor also form constitutive oligomers with themselves and with the secretin receptor. We prepared tagged constructs expressing Renilla reniformis luciferase, yellow fluorescent protein, or cyan fluorescent protein at the carboxyl terminus of VPAC1, VPAC2, and secretin receptors, and performed BRET and morphologic fluorescence resonance energy transfer (FRET) studies with all combinations. The specificity of the BRET and FRET signals was confirmed by control studies. These constructs bound their natural ligands specifically and saturably, with these agonists able to elicit full cAMP responses. BRET studies showed that, like the secretin receptor, both VPAC receptors exhibited constitutive homo-oligomerization in COS cells. Unlike secretin receptor oligomers that were unaffected by ligand binding, the VPAC receptor homo-oligomers were modulated by vasoactive intestinal polypeptide. In addition, each of these three receptors formed hetero-oligomers with each other. The VPAC1-VPAC2 hetero-oligomers were modulated by vasoactive intestinal polypeptide binding, whereas the secretin-VPAC1 and secretin-VPAC2 receptor hetero-oligomers were unaffected by ligand treatment. Morphologic FRET studies demonstrated that each of the homo-oligomers and the VPAC1-VPAC2 receptor hetero-oligomers reached the cell surface, where receptor interactions were clear. However, coexpression of secretin receptors with either type of VPAC receptor resulted in intracellular trapping of the hetero-oligomeric complexes within the biosynthetic pathway. These studies provide new insight into the ability of family B G protein-coupled receptors to associate with each other in cells.Plasma membrane receptors represent a critically important interface between circulating and extracellular hormones and neurotransmitters and the cell's intracellular signaling cascades and effector machinery. We are beginning to recognize that the specificity and activity of ligand-receptor interaction at this critical interface can be affected by a variety of factors, including covalent modifications of the receptor and bimolecular interactions with it. One group of such interactions is the dimerization or oligomerization with the same or other receptors

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The N-Terminal Extracellular Domain 23−60 of the Calcitonin Receptor-Like Receptor in Chimeras with the Parathyroid Hormone Receptor Mediates Association with Receptor Activity-Modifying Protein 1

Cited by 45 publications

References 18 publications

Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models

Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models

Phosphorylated Tau Interacts with c-Jun N-terminal Kinase-interacting Protein 1 (JIP1) in Alzheimer Disease

Constitutive Formation of Oligomeric Complexes between Family B G Protein-Coupled Vasoactive Intestinal Polypeptide and Secretin Receptors

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