Functional Modulation of the Glutamate Transporter Variant GLT1b by the PDZ Domain Protein PICK1

Søgaard, Rikke; Borre, Lars; Braunstein, Thomas Hartig; Madsen, Kenneth L.; MacAulay, Nanna

doi:10.1074/jbc.m113.471128

Cited by 21 publications

(15 citation statements)

References 55 publications

(68 reference statements)

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“… 47 PICK1 increases EAAT2b mediated leak current, also impacting glutamatergic neurotransmission. 49 Finally, EAAT2b also interacts with PSD95, allowing for transporter clustering at the postsynaptic density, thus increasing transporter activity. 50 …”

Section: Basic Biology Of Glutamate Transportersmentioning

confidence: 99%

The role of glutamate transporters in the pathophysiology of neuropsychiatric disorders

2017

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Altered glutamate transporter expression is a common feature of many neuropsychiatric conditions, including schizophrenia. Excitatory amino acid transporters (EAATs) are responsible for the reuptake of glutamate, preventing non-physiological spillover from the synapse. Postmortem studies have revealed significant dysregulation of EAAT expression in various brain regions at the cellular and subcellular level. Recent animal studies have also demonstrated a role for glutamate spillover as a mechanism of disease. In this review, we describe current evidence for the role of glutamate transporters in regulating synaptic plasticity and transmission. In neuropsychiatric conditions, EAAT splice variant expression is altered. There are changes in the localization of the transporters and disruption of the metabolic and structural protein network that supports EAAT activity. This results in aberrant neuroplasticity and excitatory signaling, contributing to the symptoms associated with neuropsychiatric disease. Understanding the complex functions of glutamate transporters will clarify the relevance of their role in the pathophysiology of neuropsychiatric disorders.

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Section: Basic Biology Of Glutamate Transportersmentioning

confidence: 99%

The role of glutamate transporters in the pathophysiology of neuropsychiatric disorders

2017

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“…There are no data to suggest that these variants alter transport function per se, but they likely contribute to differential protein expression, localization, and/or trafficking ( Holmseth et al, 2009 ). For example, GLT1a but not GLT1b is detected in neurons, and GLT-1b contains a PDZ domain absent in GLT1a ( Holmseth et al, 2009 ; Sogaard et al, 2013 ).…”

Section: Eaat2/glt-1mentioning

confidence: 99%

Glutamate Transport: A New Bench to Bedside Mechanism for Treating Drug Abuse

Spencer

Kalivas

2017

International Journal of Neuropsychopharmacology

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Drug addiction has often been described as a “hijacking” of the brain circuits involved in learning and memory. Glutamate is the principal excitatory neurotransmitter in the brain, and its contribution to synaptic plasticity and learning processes is well established in animal models. Likewise, over the past 20 years the addiction field has ascribed a critical role for glutamatergic transmission in the development of addiction. Chronic drug use produces enduring neuroadaptations in corticostriatal projections that are believed to contribute to a maladaptive deficit in inhibitory control over behavior. Much of this research focuses on the role played by ionotropic glutamate receptors directly involved in long-term potentiation and depression or metabotropic receptors indirectly modulating synaptic plasticity. Importantly, the balance between glutamate release and clearance tightly regulates the patterned activation of these glutamate receptors, emphasizing an important role for glutamate transporters in maintaining extracellular glutamate levels. Five excitatory amino acid transporters participate in active glutamate reuptake. Recent evidence suggests that these glutamate transporters can be modulated by chronic drug use at a variety of levels. In this review, we synopsize the evidence and mechanisms associated with drug-induced dysregulation of glutamate transport. We then summarize the preclinical and clinical data suggesting that glutamate transporters offer an effective target for the treatment of drug addiction. In particular, we focus on the role that altered glutamate transporters have in causing drug cues and contexts to develop an intrusive quality that guides maladaptive drug seeking behaviors.

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“…Protein interacting with kinase C1 (PICK1) is a membrane protein composed of a N‐terminal PDZ domain and a C‐terminal BAR domain, and is expressed highly in the brain and peripheral tissues . It functions as an intracellular trafficking protein involved in the internalization of amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate (AMPA) type receptors which are localized on the surface of neurons and mediate synaptic communication . Down regulation of surface AMPA receptors on neurons reduces synaptic communication leading to cognitive impairment in progressive neurodegenerative diseases such as Alzheimer disease .…”

Section: Introductionmentioning

confidence: 99%

“…1,2 It functions as an intracellular trafficking protein involved in the internalization of amino-3hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) type receptors which are localized on the surface of neurons and mediate synaptic communication. 3,4 Down regulation of surface AMPA receptors on neurons reduces synaptic communication leading to cognitive impairment in progressive neurodegenerative diseases such as Alzheimer disease. 5 GluA2 is a subunit of AMPA type receptors and is composed of an extracellular N-terminal ligand binding domain, a transmembrane domain, and an intracellular C-terminal domain.…”

Section: Introductionmentioning

confidence: 99%

Lock and chop: A novel method for the generation of a PICK1 PDZ domain and piperidine‐based inhibitor co‐crystal structure

et al. 2018

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The membrane protein interacting with kinase C1 (PICK1) plays a trafficking role in the internalization of neuron receptors such as the amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate (AMPA) receptor. Reduction of surface AMPA type receptors on neurons reduces synaptic communication leading to cognitive impairment in progressive neurodegenerative diseases such as Alzheimer disease. The internalization of AMPA receptors is mediated by the PDZ domain of PICK1 which binds to the GluA2 subunit of AMPA receptors and targets the receptor for internalization through endocytosis, reducing synaptic communication. We planned to block the PICK1‐GluA2 protein–protein interaction with a small molecule inhibitor to stabilize surface AMPA receptors as a therapeutic possibility for neurodegenerative diseases. Using a fluorescence polarization assay, we identified compound BIO124 as a modest inhibitor of the PICK1‐GluA2 interaction. We further tried to improve the binding affinity of BIO124 using structure‐aided drug design but were unsuccessful in producing a co‐crystal structure using previously reported crystallography methods for PICK1. Here, we present a novel method through which we generated a co‐crystal structure of the PDZ domain of PICK1 bound to BIO124.

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Functional Modulation of the Glutamate Transporter Variant GLT1b by the PDZ Domain Protein PICK1

Cited by 21 publications

References 55 publications

The role of glutamate transporters in the pathophysiology of neuropsychiatric disorders

The role of glutamate transporters in the pathophysiology of neuropsychiatric disorders

Glutamate Transport: A New Bench to Bedside Mechanism for Treating Drug Abuse

Lock and chop: A novel method for the generation of a PICK1 PDZ domain and piperidine‐based inhibitor co‐crystal structure

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