Mpdz is a quantitative trait gene for drug withdrawal seizures

Shirley, Renee L.; Walter, Nicole A.R.; Reilly, Matthew T.; Fehr, Christoph; Buck, Kari J.

doi:10.1038/nn1271

Cited by 116 publications

(112 citation statements)

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“…Disruption of 5-HT 2A receptor signaling is implicated in several prevalent psychiatric disorders (6)(7)(8)(9)(10)(11), and the underlying effect of these alterations of serotonergic signaling may involve structural changes in synapses, which may alter neural circuits. Additionally, kalirin has reduced mRNA expression in the cortex of schizophrenia patients (42), and MUPP1 has been genetically associated with drug withdrawal seizures (43). Thus, the signaling pathway we describe here may be important in the pathogenesis of a number of psychiatric disorders.…”

Section: Discussionmentioning

confidence: 82%

Rapid modulation of spine morphology by the 5-HT _2A serotonin receptor through kalirin-7 signaling

Jones¹,

Srivastava²,

Allen³

et al. 2009

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

177

168

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The 5-HT2A serotonin receptor is the most abundant serotonin receptor subtype in the cortex and is predominantly expressed in pyramidal neurons. The 5-HT 2A receptor is a target of several hallucinogens, antipsychotics, anxiolytics, and antidepressants, and it has been associated with several psychiatric disorders, conditions that are also associated with aberrations in dendritic spine morphogenesis. However, the role of 5-HT 2A receptors in regulating dendritic spine morphogenesis in cortical neurons is unknown. Here we show that the 5-HT 2A receptor is present in a subset of spines, in addition to dendritic shafts. It colocalizes with PSD-95 and with multiple PDZ protein-1 (MUPP1) in a subset of dendritic spines of rat cortical pyramidal neurons. MUPP1 is enriched in postsynaptic density (PSD) fractions, is targeted to spines in pyramidal neurons, and enhances the localization of 5-HT 2A receptors to the cell periphery. 5-HT2A receptor activation by the 5-HT 2 receptor agonist DOI induced a transient increase in dendritic spine size, as well as phosphorylation of p21-activated kinase (PAK) in cultured cortical neurons. PAK is a downstream target of the neuronal Rac guanine nucleotide exchange factor (RacGEF) kalirin-7 that is important for spine remodeling. Kalirin-7 regulates dendritic spine morphogenesis in neurons but its role in neuromodulator signaling has not been investigated. We show that peptide interference that prevents the localization of kalirin-7 to the postsynaptic density disrupts DOI-induced PAK phosphorylation and spine morphogenesis. These results suggest a potential role for serotonin signaling in modulating spine morphology and kalirin-7's function at cortical synapses.GPCR ͉ neuromodulator ͉ PAK ͉ Rac ͉ synapse D endritic spine morphogenesis is an important component of structural plasticity in the mammalian forebrain. Changes in dendritic spine shape, size, and number underlie synaptic functional changes and accompany neuronal development, learning and memory, and behavior (1). Additionally, abnormal spine morphogenesis has been associated with many neurodevelopmental, neuropsychiatric, and neurodegenerative diseases, suggesting the importance of appropriate development, plasticity, and maintenance of these structures to neuronal function (2). Spine morphogenesis relies on alterations in the actin cytoskeleton, but the molecular mechanisms that regulate this process are just beginning to be uncovered. The role of neuromodulators, in particular of serotonin, in spine remodeling is not well understood.The 5-HT 2A receptor is the most abundantly expressed serotonin receptor subtype in the cortex, and it is predominantly expressed in pyramidal neurons (3-5). It is a target of several hallucinogens, antipsychotics, anxiolytics, and antidepressants, and it has been functionally and genetically associated with schizophrenia, autism, attention-deficit/hyperactivity disorder, and affective disorders (6-11). 5-HT 2A receptors are expressed late in development, coinciding with the period of synapto...

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Section: Discussionmentioning

confidence: 82%

Rapid modulation of spine morphology by the 5-HT _2A serotonin receptor through kalirin-7 signaling

Jones¹,

Srivastava²,

Allen³

et al. 2009

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

177

168

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“…Recently, MUPP1 has been shown to be robustly up-regulated by hypertonicity and to be important in the osmotic stress response in tight junctions of kidney cells (51). Finally, altered MUPP1 expression levels have been shown in mice with high predisposition to alcohol and barbiturate physical dependence and withdrawal (52). Taken together, MUPP1 expression levels appear to be highly regulated in several physiological and pathological situations.…”

Section: Discussionmentioning

confidence: 98%

The PDZ Protein Mupp1 Promotes Gi Coupling and Signaling of the Mt1 Melatonin Receptor

Guillaume

Daulat

Maurice

et al. 2008

Journal of Biological Chemistry

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The concept of organized networks has emerged in the field of cellular signaling in the last few years. Assembling the different partners in close proximity optimizes the spatial and temporal organization and the specificity of the cellular response. The assembly of these multimolecular complexes occurs through the interaction of modular domains recognizing their target counterparts. PDZ domains are widely spread modules exhibiting this function. Data bank exploration with SMART (1) identifies 584 PDZ domains in 328 different proteins in the human genome.G protein-coupled receptors (GPCRs) 5 constitute the largest family of membrane receptors, and many of the more than 750 members have been shown to interact with PDZ domain-containing proteins, either constitutively or upon agonist activation (2). Binding of PDZ proteins to GPCRs has been reported to primarily regulate subcellular localization, trafficking, and stability of receptors (3). For instance, binding of MUPP1 and syntrophins to the ␥-aminobutyric acid type B (GABA B ) receptor and the ␣ 1D -adrenergic receptor, respectively, significantly increases receptor stability (4, 5). In other cases, PDZ scaffolds determine the subcellular localization of GPCRs (6) and receptor endocytosis as shown for PSD-95 and the 5-HT 2A serotonin and ␤ 1 -adrenergic receptors (7,8). PDZ proteins, such as NHERF and hScrib, are also important for the recycling of receptors to the cell surface (9 -11).Binding of PDZ proteins to GPCRs also modulates receptor signaling by assembling proteins involved in signal transduction. NHERF family proteins are known to regulate the activity of the Na ϩ /H ϩ exchanger through association with NHERF-1 (12) and to form a ternary complex with phospholipase C␤3 and GPCRs, which enhances the signaling efficiency of the receptor-mediated activation of the phospholipase C␤/Ca 2ϩ pathway (13-15). Binding of GIPC (GAIP-interacting protein, COOH terminus) to the COOH terminus of the D3 dopamine and the ␤ 1 -adrenergic receptor (16) decreased G␣ i -mediated signaling of these receptors most likely through RGS19, which binds to GIPC (17). Further examples of PDZ scaffolds that regulate GPCR signaling include a ternary complex formation around the PDZ scaffold MAGI-3, which binds to the GPCR frizzled-4 and Ltap to regulate the JNK signaling cascade (18), as well as PDZ-domain-containing Rho guanine nucleotide exchange factors that interact with lysophosphatidic acid 1 and 2 receptors to activate RhoA (19).

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“…They appear to have both structural and signaling roles within the cell and aid in localizing and coupling components of specific signal transduction pathways at specific subcellular locations. Another PDZ domain protein, multiple PDZ domain protein (Mpdz), has been identified as a QTG for alcohol and pentobarbital withdrawal seizures in mice (Shirley et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Identification of Candidate Genes for Alcohol Preference by Expression Profiling of Congenic Rat Strains

Carr

Kimpel

Liang

et al. 2007

Alcoholism Clin & Exp Res

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Background-A highly significant quantitative trait locus (QTL) on chromosome 4 that influenced alcohol preference was identified by analyzing crosses between the iP and iNP rats. Congenic strains in which the iP chromosome 4 QTL interval was transferred to the iNP (NP.P) exhibited the expected increase in alcohol consumption compared with the iNP background strain. This study was undertaken to identify genes in the chromosome 4 QTL interval that might contribute to the differences in alcohol consumption between the alcohol-naïve congenic and background strains.

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Mpdz is a quantitative trait gene for drug withdrawal seizures

Cited by 116 publications

References 11 publications

Rapid modulation of spine morphology by the 5-HT _2A serotonin receptor through kalirin-7 signaling

Rapid modulation of spine morphology by the 5-HT _2A serotonin receptor through kalirin-7 signaling

The PDZ Protein Mupp1 Promotes Gi Coupling and Signaling of the Mt1 Melatonin Receptor

Identification of Candidate Genes for Alcohol Preference by Expression Profiling of Congenic Rat Strains

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Mpdz is a quantitative trait gene for drug withdrawal seizures

Cited by 116 publications

References 11 publications

Rapid modulation of spine morphology by the 5-HT 2A serotonin receptor through kalirin-7 signaling

Rapid modulation of spine morphology by the 5-HT 2A serotonin receptor through kalirin-7 signaling

The PDZ Protein Mupp1 Promotes Gi Coupling and Signaling of the Mt1 Melatonin Receptor

Identification of Candidate Genes for Alcohol Preference by Expression Profiling of Congenic Rat Strains

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Rapid modulation of spine morphology by the 5-HT _2A serotonin receptor through kalirin-7 signaling

Rapid modulation of spine morphology by the 5-HT _2A serotonin receptor through kalirin-7 signaling