| PICK1 |
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| 1 | | Neuroreport 2004 Aug 15: 1965-7 |
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| PMID | 15305146 |
| Title | Association study of PICK1 rs3952 polymorphism and schizophrenia. |
| Abstract | Protein interacting with C-kinase-1 (PICKl) plays an important role in the targeting and clustering of neuronal receptors and amine transporters. The PICK1 gene may play a role in conferring susceptibility to schizophrenia as it has been mapped to chromosome 22q13.1, a region thought to contain a gene for schizophrenia. We tested the hypothesis that an allelic variant of the PICK1 gene was associated with a diagnosis of schizophrenia. The PICK1 rs3952 polymorphism was genotyped in 225 schizophrenia and 260 controls. Results demonstrated that the PICK1 rs3952 genotype and allele distribution was significantly different between the two groups. The positive association suggests that the PICK1 gene may play a role in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 2 | | J. Neurosci. Res. 2005 Mar 79: 868-78 |
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| PMID | 15696539 |
| Title | mRNA expression of AMPA receptors and AMPA receptor binding proteins in the cerebral cortex of elderly schizophrenics. |
| Abstract | L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate the majority of the fast excitatory transmission in the CNS. To determine whether gene expression of AMPARs and/or AMPAR binding proteins, which control response/sensitivity of AMPAR-bearing neurons to glutamate, are altered in schizophrenia, mRNA expression and abundance of AMPAR subunits (GluR1-4) and several AMPAR binding proteins (SAP97, PICK1, GRIP, ABP) were measured in the dorsolateral prefrontal cortex (DLPFC) and the occipital cortex of elderly schizophrenia patients (n = 36) and matched normal controls (n = 26) by quantitative real-time PCR. The mRNA expression of GluR1, GluR4, and GRIP in the DLPFC and expression of the GluR4, GRIP, and ABP in the occipital cortex were significantly elevated in schizophrenics. GluR1 and ABP mRNA expression in the occipital cortex and GluR2, GluR3, SAP97, and PICK1 expression in either cortical area were not significantly altered. The data also demonstrated significant differences in the abundances of mRNAs encoding GluR1-4 subunits (GluR2 > GluR3 > GluR1 > GluR4) and of AMPAR binding proteins (SAP97 > PICK1 > GRIP > ABP) in both diagnostic groups. GluR2 (58-64%) and GluR3 (24-29%) were the major components of the AMPAR mRNA in both cortical areas, implying that the major AMPAR complexes in the human cortex are probably those containing GluR2 and GluR3 subunits. Small but significant differences in the amounts of GluR2, GluR3, and GRIP mRNAs were detected between the two cortical areas: more GluR3 and GRIP but less GluR2 were detected in the DLPFC than in the occipital cortex. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 3 | | J. Neurosci. Res. 2005 Mar 79: 868-78 |
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| PMID | 15696539 |
| Title | mRNA expression of AMPA receptors and AMPA receptor binding proteins in the cerebral cortex of elderly schizophrenics. |
| Abstract | L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate the majority of the fast excitatory transmission in the CNS. To determine whether gene expression of AMPARs and/or AMPAR binding proteins, which control response/sensitivity of AMPAR-bearing neurons to glutamate, are altered in schizophrenia, mRNA expression and abundance of AMPAR subunits (GluR1-4) and several AMPAR binding proteins (SAP97, PICK1, GRIP, ABP) were measured in the dorsolateral prefrontal cortex (DLPFC) and the occipital cortex of elderly schizophrenia patients (n = 36) and matched normal controls (n = 26) by quantitative real-time PCR. The mRNA expression of GluR1, GluR4, and GRIP in the DLPFC and expression of the GluR4, GRIP, and ABP in the occipital cortex were significantly elevated in schizophrenics. GluR1 and ABP mRNA expression in the occipital cortex and GluR2, GluR3, SAP97, and PICK1 expression in either cortical area were not significantly altered. The data also demonstrated significant differences in the abundances of mRNAs encoding GluR1-4 subunits (GluR2 > GluR3 > GluR1 > GluR4) and of AMPAR binding proteins (SAP97 > PICK1 > GRIP > ABP) in both diagnostic groups. GluR2 (58-64%) and GluR3 (24-29%) were the major components of the AMPAR mRNA in both cortical areas, implying that the major AMPAR complexes in the human cortex are probably those containing GluR2 and GluR3 subunits. Small but significant differences in the amounts of GluR2, GluR3, and GRIP mRNAs were detected between the two cortical areas: more GluR3 and GRIP but less GluR2 were detected in the DLPFC than in the occipital cortex. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 4 | | Synapse 2006 Dec 60: 585-98 |
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| PMID | 16983646 |
| Title | Lamina-specific abnormalities of AMPA receptor trafficking and signaling molecule transcripts in the prefrontal cortex in schizophrenia. |
| Abstract | Ampakines, positive AMPA receptor modulators, can improve cognitive function in schizophrenia, and enhancement of AMPA receptor-mediated currents by them potentiates the activity of antipsychotics. In vitro studies have revealed that trafficking of AMPA receptors is mediated by specific interactions of a complex network of proteins that also target and anchor them at the postsynaptic density (PSD). The aim of this study was to determine whether there are abnormalities of the molecules associated with trafficking and localization of AMPA receptors at the PSD in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. We analyzed AMPA receptor expression in DLPFC in schizophrenia, major depression, bipolar disorder, and a control group, by examining transcript levels of all four AMPA receptor subunits by in situ hybridization. We found decreased GluR2 subunit expression in all three illnesses, decreased GluR3 in major depression, and decreased GluR4 in schizophrenia. However, autoradiography experiments showed no changes in AMPA receptor binding; thus, we hypothesized that these changes in receptor subunit stoichiometry do not alter binding to the assembled receptor, but rather intracellular processing. In situ hybridization for AMPA-trafficking molecules showed decreased expression of PICK1 and increased expression of stargazin in DLPFC in schizophrenia, both restricted to large cells of cortical layer III. These data suggest that AMPA-mediated glutamatergic neurotransmission is compromised in schizophrenia, particularly at the level of AMPA-related PSD proteins that mediate AMPA receptor trafficking, synaptic surface expression, and intracellular signaling. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 5 | | Trends Pharmacol. Sci. 2006 Nov 27: 574-9 |
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| PMID | 17011050 |
| Title | The schizophrenic faces of PICK1. |
| Abstract | Schizophrenia is a grave psychiatric disorder with psychotic symptoms and an enigmatic etiology. Family studies have strongly indicated that genetic risk factors have a role in this disease. Recent findings, together with previously established evidence, highlight the PDZ-domain-containing protein interacting with C-kinase 1 (PICK1) as a promising candidate for a schizophrenia susceptibility gene. Here, we outline possible molecular mechanisms, discuss clinical case-studies that indicate an unexpected role of PICK1 in schizophrenia and discuss potential avenues for pharmacological manipulation of PICK1. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 6 | | Trends Pharmacol. Sci. 2006 Nov 27: 574-9 |
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| PMID | 17011050 |
| Title | The schizophrenic faces of PICK1. |
| Abstract | Schizophrenia is a grave psychiatric disorder with psychotic symptoms and an enigmatic etiology. Family studies have strongly indicated that genetic risk factors have a role in this disease. Recent findings, together with previously established evidence, highlight the PDZ-domain-containing protein interacting with C-kinase 1 (PICK1) as a promising candidate for a schizophrenia susceptibility gene. Here, we outline possible molecular mechanisms, discuss clinical case-studies that indicate an unexpected role of PICK1 in schizophrenia and discuss potential avenues for pharmacological manipulation of PICK1. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 7 | | Mol. Psychiatry 2006 Feb 11: 150-7 |
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| PMID | 16314870 |
| Title | Serine racemase binds to PICK1: potential relevance to schizophrenia. |
| Abstract | Accumulating evidence from both genetic and clinico-pharmacological studies suggests that D-serine, an endogenous coagonist to the NMDA subtype glutamate receptor, may be implicated in schizophrenia (SZ). Although an association of genes for D-serine degradation, such as D-amino acid oxidase and G72, has been reported, a role for D-serine in SZ has been unclear. In this study, we identify and characterize protein interacting with C-kinase (PICK1) as a protein interactor of the D-serine synthesizing enzyme, serine racemase (SR). The binding of endogenous PICK1 and SR requires the PDZ domain of PICK1. The gene coding for PICK1 is located at chromosome 22q13, a region frequently linked to SZ. In a case-control association study using well-characterized Japanese subjects, we observe an association of the PICK1 gene with SZ, which is more prominent in disorganized SZ. Our findings implicating PICK1 as a susceptibility gene for SZ are consistent with a role for D-serine in the disease. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 8 | | Neurosci. Res. 2007 Jun 58: 145-8 |
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| PMID | 17367885 |
| Title | PICK1 is not a susceptibility gene for schizophrenia in a Japanese population: association study in a large case-control population. |
| Abstract | The protein interacting with C-kinase 1 (PICK1) has been implicated in the susceptibility to schizophrenia. PICK1 interacts with enzymes and receptors that play roles in the pathogenesis of schizophrenia via glutamatergic dysfunction. Recently, two studies reported associations between schizophrenia and two PICK1 gene polymorphisms, rs3952 in Chinese and Japanese populations and rs2076369 in a Japanese population. We attempted to confirm these associations in a case-control study of 1765 Japanese patients with schizophrenia and 1851 Japanese control subjects. Neither polymorphism was associated with schizophrenia (rs3952, p=0.755; rs2076369, p=0.997). A haplotype block with these polymorphisms spanning the 5' region of the PICK1 gene showed high linkage disequilibrium in the Japanese population (D'=0.98, r(2)=0.34); however, neither haplotype was significantly associated with schizophrenia. We conclude that the common haplotypes and polymorphisms of the PICK1 gene identified thus far are unlikely to contribute to genetic susceptibility to schizophrenia in the Japanese population. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 9 | | Biol. Psychiatry 2008 May 63: 997-1000 |
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| PMID | 18191108 |
| Title | Modulation of D-serine levels in brains of mice lacking PICK1. |
| Abstract | D-serine is an endogenous coagonist of the N-methyl-D-aspartate subtype glutamate receptor. Genetic association studies have implicated genes coding for enzymes associated with D-serine metabolism in schizophrenia and bipolar disorder.
Protein expression of serine racemase (SR) and its binding partner, protein interacting with C-kinase (PICK1), were examined by Western blotting in brains from wildtype and PICK1 knockout mice. Levels of D-serine in wildtype and PICK1 mice were also examined by an established high-pressure liquid chromatography protocol.
Expression of SR and PICK1 proteins was developmentally regulated. Although no change was observed in the level of SR protein, levels of D-serine were selectively decreased in the forebrain of neonatal PICK1 knockout mice, compared with those in wildtype mice.
PICK1 may be involved in the regulation of brain D-serine levels and SR in a spatially and temporally specific manner. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 10 | | J. Neurochem. 2008 Aug 106: 1027-34 |
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| PMID | 18429931 |
| Title | Zinc binding site in PICK1 is dominantly located at the CPC motif of its PDZ domain. |
| Abstract | PICK1 (protein interacting with Ckinase 1) containing a PDZ domain, a BAR domain, and two short acidic regions is as an adaptor protein that plays an important role in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor trafficking, cell morphology and migration, as well as in some diseases such as cancer, schizophrenia and pain. To better understand the physiological function of PICK1, we expressed the recombinant PICK1 and its truncated mutants in E.coli, and measured their zinc binding properties by fluorescence and competition assay. It is shown that PICK1 has one Zn2+-binding site. The Zn2+-binding properties of PICK1 are not appreciably affected after the removal of BARC domain (involving BAR domain and C-terminal acidic region). Deleting the N-terminal acidic region of NPDZ domain (involving PDZ domain and N-terminal acidic region) in PICK1 impairs its Zn2+-binding capacity. The mutation of the CPC (Cys-Pro-Cys) motif in the PDZ domain of PICK1 abolishes the ability of Zn2+-binding. In addition, Zn2+ can enhance the lipid-binding ability of PDZ domain as observed in both protein-lipid overlay assay and fluorescence analysis. The results presented in this report suggested that Zn2+ plays a regulatory role in the trafficking of PICK1 from the cytoplasm to cell membrane. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 11 | | Schizophr. Res. 2010 Jul 120: 236-7 |
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| PMID | 20385472 |
| Title | Elevated PICK1 mRNA in schizophrenia increased SRR mRNA in suicide. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 12 | | Proteins 2012 May 80: 1393-408 |
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| PMID | 22275068 |
| Title | The binding affinities of proteins interacting with the PDZ domain of PICK1. |
| Abstract | Protein interacting with C kinase (PICK1) is well conserved throughout evolution and plays a critical role in synaptic plasticity by regulating the trafficking and posttranslational modification of its interacting proteins. PICK1 contains a single PSD95/DlgA/Zo-1 (PDZ) protein-protein interaction domain, which is promiscuous and shown to interact with over 60 proteins, most of which play roles in neuronal function. Several reports have suggested the role of PICK1 in disorders such as epilepsy, pain, brain trauma and stroke, drug abuse and dependence, schizophrenia and psychosis. Importantly, lead compounds that block PICK1 interactions are also now becoming available. Here, a new modeling approach was developed to investigate binding affinities of PDZ interactions. Using these methods, the binding affinities of all major PICK1 interacting proteins are reported and the effects of PICK1 mutations on these interactions are described. These modeling methods have important implications in defining the binding properties of proteins interacting with PICK1 as well as the general structural requirements of PDZ interactions. The study also provides modeling methods to support in the drug design of ligands for PDZ domains, which may further aid in development of the family of PDZ domains as a drug target. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 13 | | PLoS ONE 2013 -1 8: e70302 |
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| PMID | 23936182 |
| Title | Population-specific haplotype association of the postsynaptic density gene DLG4 with schizophrenia, in family-based association studies. |
| Abstract | The post-synaptic density (PSD) of glutamatergic synapses harbors a multitude of proteins critical for maintaining synaptic dynamics. Alteration of protein expression levels in this matrix is a marked phenomenon of neuropsychiatric disorders including schizophrenia, where cognitive functions are impaired. To investigate the genetic relationship of genes expressed in the PSD with schizophrenia, a family-based association analysis of genetic variants in PSD genes such as DLG4, DLG1, PICK1 and MDM2, was performed, using Japanese samples (124 pedigrees, n = 376 subjects). Results showed a significant association of the rs17203281 variant from the DLG4 gene, with preferential transmission of the C allele (p = 0.02), although significance disappeared after correction for multiple testing. Replication analysis of this variant, found no association in a Chinese schizophrenia cohort (293 pedigrees, n = 1163 subjects) or in a Japanese case-control sample (n = 4182 subjects). The DLG4 expression levels between postmortem brain samples from schizophrenia patients showed no significant changes from controls. Interestingly, a five marker haplotype in DLG4, involving rs2242449, rs17203281, rs390200, rs222853 and rs222837, was enriched in a population specific manner, where the sequences A-C-C-C-A and G-C-C-C-A accumulated in Japanese (p = 0.0009) and Chinese (p = 0.0007) schizophrenia pedigree samples, respectively. However, this could not be replicated in case-control samples. None of the variants in other examined candidate genes showed any significant association in these samples. The current study highlights a putative role for DLG4 in schizophrenia pathogenesis, evidenced by haplotype association, and warrants further dense screening for variants within these haplotypes. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 14 | | Mol. Psychiatry 2013 May 18: 557-67 |
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| PMID | 22801410 |
| Title | Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion. |
| Abstract | Perturbation of Disrupted-In-Schizophrenia-1 (DISC1) and D-serine/NMDA receptor hypofunction have both been implicated in the pathophysiology of schizophrenia and other psychiatric disorders. In the present study, we demonstrate that these two pathways intersect with behavioral consequences. DISC1 binds to and stabilizes serine racemase (SR), the enzyme that generates D-serine, an endogenous co-agonist of the NMDA receptor. Mutant DISC1 fails to bind to SR, facilitating ubiquitination and degradation of SR and a decrease in D-serine production. To elucidate DISC1-SR interactions in vivo, we generated a mouse model of selective and inducible expression of mutant DISC1 in astrocytes, the main source of D-serine in the brain. Expression of mutant DISC1 downregulates endogenous DISC1 and decreases protein but not mRNA levels of SR, resulting in diminished production of D-serine. In contrast, mutant DISC1 does not alter levels of ALDH1L1, connexins, GLT-1 or binding partners of DISC1 and SR, LIS1 or PICK1. Adult male and female mice with lifelong expression of mutant DISC1 exhibit behavioral abnormalities consistent with hypofunction of NMDA neurotransmission. Specifically, mutant mice display greater responses to an NMDA antagonist, MK-801, in open field and pre-pulse inhibition of the acoustic startle tests and are significantly more sensitive to the ameliorative effects of D-serine. These findings support a model wherein mutant DISC1 leads to SR degradation via dominant negative effects, resulting in D-serine deficiency that diminishes NMDA neurotransmission thus linking DISC1 and NMDA pathophysiological mechanisms in mental illness. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 15 | | Synapse 2013 Aug 67: 532-40 |
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| PMID | 23436724 |
| Title | Protein interacting with C kinase and neurological disorders. |
| Abstract | Best known for its interaction with the ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluA2 and for its influence on excitatory synapse activity, the protein interacting with C kinase, PICK1, is the focus of considerable attention from neurobiologists. Indeed, this PSD-95/DlgA/ZO-1 (PDZ) domain-containing protein has been shown to interact with a wide variety of neurotransmitter receptors, transporters, and enzymes, including glutamate and nicotinic acetylcholine receptors, dopamine and glutamate transporters, and the enzyme serine racemase. Through its lipid binding domain, PICK1 is targeted to the inner surface of the cell membrane where it contributes to anchoring these partners and thereby influences their synaptic localization and function. Under pathological conditions, the regulation of some PICK1-interacting partners is altered, pointing to an involvement of PICK1 in neurological disorders. Also, genetic or pharmacological manipulations of PICK1 expression, localization, or function have been shown to influence several physiological or pathological processes in which putative PICK1 partners are involved. This review will summarize recent experimental observations that highlight the involvement of PICK1 in neurological disorders, including schizophrenia, Parkinson's disease, epilepsy, chronic pain, drug abuse, and amyotrophic lateral sclerosis. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 16 | | J. Neurosci. 2015 Apr 35: 6429-43 |
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| PMID | 25904794 |
| Title | Protein Interacting with C-Kinase 1 Deficiency Impairs Glutathione Synthesis and Increases Oxidative Stress via Reduction of Surface Excitatory Amino Acid Carrier 1. |
| Abstract | Protein interacting with C-kinase 1 (PICK1) has received considerable attention, because it interacts with a broad range of neurotransmitter receptors, transporters, and enzymes and thereby influences their localization and function in the CNS. Although it is suggested that putative partners of PICK1 are involved in neurological diseases such as schizophrenia, Parkinson's disease, chronic pain, and amyotrophic lateral sclerosis, the functions of PICK1 in neurological disorders are not clear. Here, we show that oxidative stress, which is tightly associated with neurological diseases, occurs in PICK1(-/-) mice. The oxidation in PICK1(-/-) mice was found selectively in neurons and was age dependent, leading to microglial activation and the release of inflammatory factors. Neurons in the cortex and hippocampus from PICK1(-/-) mice showed increased vulnerability to oxidants and reduced capacity to metabolize reactive oxygen species (ROS); this was caused by reduced glutathione content and impaired cysteine transport. The dysregulated expression of glutathione was attributed to a decrease of the surface glutamate transporter excitatory amino acid carrier 1 (EAAC1). Overexpression of PICK1 could rescue the surface expression of EAAC1 and ameliorate the glutathione deficit in PICK1(-/-) neurons. Finally, reduced surface EAAC1 was associated with defective Rab11 activity. Transfection with dominant-negative Rab11 effectively suppressed surface EAAC1 and increased ROS production. Together, these results indicate that PICK1 is a crucial regulator in glutathione homeostasis and may play important roles in oxidative stress and its associated neurodegenerative diseases. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 17 | | Meta Gene 2015 Sep 5: 135-9 |
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| PMID | 26925374 |
| Title | Secondary association of PDLIM5 with paranoid schizophrenia in Emirati patients. |
| Abstract | Schizophrenia is a clinically and genetically heterogeneous disorder of unknown etiology. PDLIM5 variants have been linked to schizophrenia and other related neuropsychiatric disorders and upregulated in the brain of schizophrenia patients suggesting a possible pathogenic role in disease progression. The aim of this study is to examine the potential association of schizophrenia in Emirati patients with previously reported variants in PDLIM5, PICK1, NRG3 or DISC1 genes. Consequently, we found a secondary association between PDLIM5 variants and the paranoid subtype of schizophrenia in Emirati Arabs suggesting that PDLIM5 may represent a determinate/marker for schizophrenia subtype specification. However, no associations were found with variants in PICK1, NRG3 or DISC1 genes. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 18 | | Neurochem. Int. 2016 Mar -1: -1 |
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| PMID | 26970394 |
| Title | Multiple faces of protein interacting with C kinase 1 (PICK1): Structure, function, and diseases. |
| Abstract | Protein interacting with C-kinase 1 (PICK1) has received considerable attention because it is the only protein that contains both PSD-95/DlgA/ZO-1 (PDZ) domain and Bin-Amphiphysin-Rvs (BAR) domain. Through PDZ and BAR domains, PICK1 binds to a large number of membrane proteins and lipid molecules, and is thereby of multiple functions. PICK1 is widely expressed in various tissues, particularly abundant in the brain and testis. In the central nervous system (CNS), PICK1 interacts with numerous neurotransmitters receptors, transporters, ion channels, and enzymes, and controls their trafficking. The best characterized function of PICK1 is that it regulates trafficking of ?-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) subunit GluA2 during long-term depression and long-term potentiation. Recent evidence shows that PICK1 participates in various diseases including neurobiological disorders, such as chronic pain, epilepsy, oxidative stress, stroke, Parkinson's disease, amyotrophic lateral sclerosis, schizophrenia, and non-neurological disorders, such as globozoospermia, breast cancer, and heart failure. In this review, we will summarize recent advances focusing on the structure and regulation of PICK1 and its functions in protein trafficking, neurological and non-neurological diseases. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
