Relationship between Alzheimer’s disease clinical stage and Gq/11 in subcellular fractions of frontal cortex

Kelly, Jeremiah F.; Storie, K.; Skamra, Carly; Bienias, Julia L.; Beck, Todd; Bennett, David A.

doi:10.1007/s00702-004-0243-7

Cited by 8 publications

(8 citation statements)

References 23 publications

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“…We next sought to characterize the cytoplasmic, DSM and DRM fractions by reprobing blots with antibodies for Rap1, G olf , G i1 , G q/11 and PLCβ1–dopamine receptor-related signaling components whose subcellular localization has previously been characterized (Canobbio et al, 2008; Donati and Rasenick, 2005; Kelly et al, 2005). Rap1, G olf , G q/11 , G i1 and PLCβ1 were all found in the DSM (Fig 2).…”

Section: 0 Resultsmentioning

confidence: 99%

Differential subcellular distribution of rat brain dopamine receptors and subtype-specific redistribution induced by cocaine

Voulalas

Schetz

Undieh

2011

Molecular and Cellular Neuroscience

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We investigated the subcellular distribution of dopamine D 1 , D 2 and D 5 receptor subtypes in rat frontal cortex, and examined whether psychostimulant-induced elevation of synaptic dopamine could alter the receptor distribution. Differential detergent solubilization and density gradient centrifugation were used to separate various subcellular fractions, followed by semi-quantitative determination of the relative abundance of specific receptor proteins in each fraction. D 1 receptors were predominantly localized to detergent-resistant membranes, and a portion of these receptors also floated on sucrose gradients. These properties are characteristic of proteins found in lipid rafts and caveolae. D 2 receptors exhibited variable distribution between cytoplasmic, detergent-soluble and detergent-resistant membrane fractions, yet were not present in buoyant membranes. Most D 5 receptor immunoreactivity was distributed into the cytoplasmic fraction, failing to sediment at forces up to 300,000g, while the remainder was localized to detergent-soluble membranes in cortex. D 5 receptors were undetectable in detergent-resistant fractions or raft-like subdomains. Following daily cocaine administration for seven days, a significant portion of D 1 receptors translocated from detergent-resistant membranes to detergent-soluble membranes and the cytoplasmic fraction. The distributions of D 5 and D 2 receptor subtypes were not significantly altered by cocaine treatment. These data imply that D 5 receptors are predominantly cytoplasmic, D 2 receptors are diffusely distributed within the cell, whereas D 1 receptors are mostly localized to lipid rafts within the rat frontal cortex. Dopamine receptor subtype localization is susceptible to modulation by pharmacological manipulations that elevate synaptic dopamine, however the functional implications of such drug-induced receptor warrant further investigation.

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Section: 0 Resultsmentioning

confidence: 99%

Differential subcellular distribution of rat brain dopamine receptors and subtype-specific redistribution induced by cocaine

Voulalas

Schetz

Undieh

2011

Molecular and Cellular Neuroscience

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“…Previous studies suggest that M 2 muscarinic receptor coupling via G i/o is preserved in AD brains (Cowburn, et al , 1992), but M 1 receptor coupling to G q/11 is reduced (Ladner, et al , 1995). Although the mechanisms contributing to a reduced coupling in AD remain unknown, it may relate to decreased levels of G q/11 (Kelly, et al , 2005). In fact, Kelly et al demonstrated a significant relationship between the levels of cognition and synaptic plasma membrane G q/11 .…”

Section: Discussionmentioning

confidence: 99%

Cortical M1 receptor concentration increases without a concomitant change in function in Alzheimer's disease

Overk

Felder

et al. 2010

Journal of Chemical Neuroanatomy

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Although the M 1 muscarinic receptor is a potential therapeutic target for Alzheimer's disease (AD) based on its wide spread distribution in brain and its association with learning and memory processes, whether its receptor response is altered during the onset of AD remains unclear. A novel [ 35 S] GTPγS binding/immunocapture assay was employed to evaluated changes in M 1 receptor function in cortical tissue samples harvested from people who had no cognitive impairment (NCI), mild cognitive impairment (MCI), or AD. M 1 -function was stable across clinical groups. However, [ 3 H]-oxotremorine-M radioligand binding studies revealed that the concentration of M 1 cortical receptors increased significantly between the NCI and AD groups. Although M 1 receptor function did not correlate with cognitive function based upon mini-mental status examination (MMSE) or global cognitive score (GCS), functional activity was negatively correlated with the severity of neuropathology determined by Braak staging and NIA-Reagan criteria for AD. Since M 1 agonists have the potential to modify the pathologic hallmarks of AD, as well as deficits in cognitive function in animal models of this disease, the present findings provide additional support for targeting the M 1 receptor as a potential therapeutic for AD.

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“…Other studies on isolated cells or subcellular fractions have used buffers containing EDTA (47,53), which may prevent the proper isolation of rafts (48). We have eliminated EDTA from our detergent-free buffer, but have added sodium fluoride and sodium orthovanadate to inhibit serine/threonine and tryrosine protein phosphatase activity.…”

Section: Discussionmentioning

confidence: 99%

Isolation of rafts from mouse brain tissue by a detergent-free method

Persaud-Sawin

Lightcap

Harry

2009

Journal of Lipid Research

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Membrane rafts are rich in cholesterol and sphingolipids and have specific proteins associated with them. Due to their small size, their identification and isolation have proved to be problematic. Their insolubility in nonionic detergents, such as Triton-X 100, at 4°C has been the most common means of isolation. However, detergent presence can produce artifacts or interfere with ganglioside distribution. The direction is therefore toward the use of detergent-free protocols. We report an optimized method of raft isolation from lipid-rich brain tissue using a detergentfree method. We compared this to Triton-X 100-based isolation along sucrose or Optiprep™ gradients using the following endpoints: low protein content, high cholesterol content, presence of Flotillin 1 (Flot1), and absence of transferrin receptor (TfR) proteins. These criteria were met in raft fractions isolated in a detergent-free buffer along a sucrose gradient of 5%/35%/42.5%. The use of optiprep gave less consistent results with respect to protein distribution. We demonstrate that clean raft fractions with minimal myelin contamination can be reproducibly obtained in the top three low-density fractions along a sucrose step gradient.-Persaud-Sawin, D-A., S. Lightcap, and G. J. Harry. Isolation of rafts from mouse brain tissue by a detergent-free method.

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Relationship between Alzheimer’s disease clinical stage and Gq/11 in subcellular fractions of frontal cortex

Cited by 8 publications

References 23 publications

Differential subcellular distribution of rat brain dopamine receptors and subtype-specific redistribution induced by cocaine

Differential subcellular distribution of rat brain dopamine receptors and subtype-specific redistribution induced by cocaine

Cortical M1 receptor concentration increases without a concomitant change in function in Alzheimer's disease

Isolation of rafts from mouse brain tissue by a detergent-free method

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