Intracellular trafficking of GABAA receptors

Barnes, Eugene M.

doi:10.1016/s0024-3205(99)00469-5

Cited by 75 publications

(48 citation statements)

References 30 publications

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“…The movement of receptors within cells requires the activity of molecules such as dynamin, a GTPase that mediates vesicle budding, and clathrin, a major constituent of the vesicle coat (8,25). Several ligand-gated ion channels, such as GABA A , are found to traffic in a dynamin-dependent fashion (43). Our experiments indicate association of the ␤2 subunit with the neuron-specific dynamin 1 isoform and with the HC of the clathrin complex.…”

Section: Interestingly Alterations In the Expression Of Nsf And Dynamentioning

confidence: 68%

Intracellular complexes of the β2 subunit of the nicotinic acetylcholine receptor in brain identified by proteomics

Kabbani

Woll

Levenson

et al. 2007

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

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Nicotine acetylcholine receptors (nAChRs) comprise a family of ligand-gated channels widely expressed in the mammalian brain. The ␤2 subunit is an abundant protein subunit critically involved in the cognitive and behavioral properties of nicotine as well as in the mechanisms of nicotine addiction. In this work, we used matrixassisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF-TOF MS/MS) to uncover protein interactions of the intracellular loop of the ␤2 subunit and components of immunoprecipitated ␤2-nAChR complexes from mouse brain. Using the ␤2-knockout mouse to exclude nonspecific binding to the ␤2 antibody, we identify 21 nAChR-interacting proteins (NIPs) expressed in brain. Western blot analysis confirmed the association between the ␤2 subunit and candidate NIPs. Based on their functional profiles, the hypothesis is suggested that the identified NIPs can regulate the trafficking and signaling of the ␤2-nAChR. Interactions of the ␤2 subunit with NIPs such as G protein ␣, G protein-regulated inducer of neurite outgrowth 1, and G proteinactivated K ؉ channel 1 suggest a link between nAChRs and cellular G protein pathways. These findings reveal intracellular interactions of the ␤2 subunit and may contribute to the understanding of the mechanisms of nAChR signaling and trafficking in neurons.mass spectrometry ͉ receptor complex N icotine is a common drug of addiction and a leading cause of preventable deaths in developed countries (1, 2). The target of nicotine is a class of nicotinic acetylcholine receptors (nAChRs) existing as pentameric channels made up of various receptor subunits and distributed throughout the brain (3). To date, 11 neuronal subunits have been identified: ␣2-␣9 and ␤2-␤4. The specific combination of these subunits confers the pharmacological and physiological properties of the nAChR (4). Studies show that Ϸ90% of the high-affinity nicotine receptor sites within the brain consist of the ␣4␤2-nAChR (5, 6). Topological analysis of nAChR subunits indicates the presence of a large, highly divergent intracellular loop (M3-M4 loop) that is implicated in trafficking and targeting properties of nAChRs (7,8). Recent analysis of a prokaryotic homolog of the nAChR family reveals that the M3-M4 loop is unique to the evolution of the nAChR in eukaryotes (9).The generation of subunit-specific knockout (KO) mice has proven valuable in defining the role of individual nAChR subunits in brain physiology and animal behavior (10). Experiments in mice lacking the ␤2 subunit (␤2 Ϫ/Ϫ ) demonstrate an important role for this receptor subunit in neuronal development and plasticity (10), protection from excitotoxicity (11), and the mechanisms underlying cognitive and social behaviors (12). ␤2 Ϫ/Ϫ mice also exhibit a loss of nicotine self-administration and nicotine-elicited firing and dopamine release from dopaminergic neurons of the ventral tegmental area (13,14). Because reexpression of the ␤2 subunit in ␤2 Ϫ/Ϫ mice was found sufficient to restore the electrophysiological and beh...

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Section: Interestingly Alterations In the Expression Of Nsf And Dynamentioning

confidence: 68%

Intracellular complexes of the β2 subunit of the nicotinic acetylcholine receptor in brain identified by proteomics

Kabbani

Woll

Levenson

et al. 2007

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

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“…NMDA receptors are trafficked to and anchored at the PSD by numerous proteins including PSD95, neuregulin, and SAP102. (Barnes, 2000;Lionel et al, 2013;Weickert et al, 2004). Similar to the DISC1 and neuregulin1 knockout mice, PSD95 homozygous KO's are not lethal, and the heterozygous animals share prepulse inhibition, hyperactivity, and enhanced LTP phenotypes (Desbonnet et al, 2009;Dyck et al, 2009;Kato et al, 2010;Le Greves et al, 2006;Yao et al, 2004).…”

Section: Data From Post-synaptic Density 95 (Psd95)mentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

108

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We propose that postmortem tissue is an underutilized substrate that may be used to translate genetic and/or preclinical studies, particularly for neuropsychiatric illnesses with complex etiologies. Postmortem brain tissues from subjects with schizophrenia have been extensively studied, and thus serve as a useful vehicle for illustrating the challenges associated with this biological substrate. Schizophrenia is likely caused by a combination of genetic risk and environmental factors that combine to create a disease phenotype that is typically not apparent until late adolescence. The complexity of this illness creates challenges for hypothesis testing aimed at understanding the pathophysiology of the illness, as postmortem brain tissues collected from individuals with schizophrenia reflect neuroplastic changes from a lifetime of severe mental illness, as well as treatment with antipsychotic medications. While there are significant challenges with studying postmortem brain, such as the postmortem interval, it confers a translational element that is difficult to recapitulate in animal models. On the other hand, data derived from animal models typically provide specific mechanistic and behavioral measures that cannot be generated using human subjects. Convergence of these two approaches has led to important insights for understanding molecular deficits and their causes in this illness. In this review, we discuss the problem of schizophrenia, review the common challenges related to postmortem studies, discuss the application of biochemical approaches to this substrate, and present examples of postmortem schizophrenia studies that illustrate the role of the postmortem approach for generating important new leads for understanding the pathophysiology of severe mental illness.

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“…To form and maintain postsynaptic clusters, neurons must possess the ability to appropriately sort, target, cluster, recycle, and degrade GABA A receptors (1). All these processes are highly regulated and have been shown to rely on the presence of the intact cytoskeleton and on the interplay of functional proteins and intracellular factors (2,3).…”

Section: Efficient Gabaergicmentioning

confidence: 99%

“…The values of the rate constants governing the entry and the exit from the desensitized state (d 2 and r 2 , respectively) were evaluated from the time course of currents evoked by long agonist application and paired pulse protocols. The value of the close-to-open rate constant (␤ 2 ) and d 2 were adjusted according to the current onset at saturating concentrations of agonist. The open to close rate constant (␣ 2 ) and the unbinding rate constant (k off ) were optimized to reproduce the decay of currents elicited by 2-ms pulses of saturating concentration of GABA and paired pulse protocols.…”

Section: Nocodazole Treatment Does Not Affect Gaba Responses To Pairedmentioning

confidence: 99%

Declusterization of GABAA Receptors Affects the Kinetic Properties of GABAergic Currents in Cultured Hippocampal Neurons

Petrini

Zacchi

Barberis

et al. 2003

Journal of Biological Chemistry

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Intracellular trafficking of GABAA receptors

Cited by 75 publications

References 30 publications

Intracellular complexes of the β2 subunit of the nicotinic acetylcholine receptor in brain identified by proteomics

Intracellular complexes of the β2 subunit of the nicotinic acetylcholine receptor in brain identified by proteomics

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

Declusterization of GABAA Receptors Affects the Kinetic Properties of GABAergic Currents in Cultured Hippocampal Neurons

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