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?2 GABAAR Trafficking and the Consequences of Human Genetic Variation.

ABSTRACT: GABA type A receptors (GABAARs) mediate the majority of fast inhibitory neurotransmission in the central nervous system (CNS). Most prevalent as heteropentamers composed of two ?, two ?, and a ?2 subunit, these ligand-gated ionotropic chloride channels are capable of extensive genetic diversity (?1-6, ?1-3, ?1-3, ?, ?, ?, ?, ?1-3). Part of this selective GABAAR assembly arises from the critical role for ?2 in maintaining synaptic receptor localization and function. Accordingly, mutations in this subunit account for over half of the known epilepsy-associated genetic anomalies identified in GABAARs. Fundamental structure-function studies and cellular pathology investigations have revealed dynamic GABAAR trafficking and synaptic scaffolding as critical regulators of GABAergic inhibition. Here, we introduce in vitro and in vivo findings regarding the specific role of the ?2 subunit in receptor trafficking. We then examine ?2 subunit human genetic variation and assess disease related phenotypes and the potential role of altered GABAAR trafficking. Finally, we discuss new-age imaging techniques and their potential to provide novel insight into critical regulatory mechanisms of GABAAR function.

SUBMITTER: Lorenz-Guertin JM

PROVIDER: S-EPMC6116786 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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γ2 GABAAR Trafficking and the Consequences of Human Genetic Variation.

Lorenz-Guertin Joshua M JM Bambino Matthew J MJ Jacob Tija C TC

Frontiers in cellular neuroscience 20180823

GABA type A receptors (GABAARs) mediate the majority of fast inhibitory neurotransmission in the central nervous system (CNS). Most prevalent as heteropentamers composed of two α, two β, and a γ2 subunit, these ligand-gated ionotropic chloride channels are capable of extensive genetic diversity (α1-6, β1-3, γ1-3, δ, 𝜀, 𝜃, π, ρ1-3). Part of this selective GABAAR assembly arises from the critical role for γ2 in maintaining synaptic receptor localization and function. Accord ...[more]

PMID: 30190672

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Project description:Variation in dispersal capacity may influence population genetic variation and relatedness of freshwater animals thus demonstrating how life-history traits influence patterns and processes that in turn influence biodiversity. The majority of studies have focused on the consequences of dispersal variation in taxa inhabiting riverine systems whose dendritic nature and upstream/downstream gradients facilitate characterizing populations along networks. We undertook extensive, large-scale investigations of the impacts of hydrological connectivity on population genetic variation in two freshwater bryozoan species whose dispersive propagules (statoblasts) are either attached to surfaces (Fredericella sultana) or are released as buoyant stages (Cristatella mucedo) and that live primarily in either lotic (F. sultana) or lentic environments (C. mucedo). Describing population genetic structure in multiple sites characterized by varying degrees of hydrological connectivity within each of three (or four) UK regions enabled us to test the following hypotheses: (1) genetic diversity and gene flow will be more influenced by hydrological connectivity in populations of C. mucedo (because F. sultana dispersal stages are retained); (2) populations of F. sultana will be characterized by greater genetic divergence than those of C. mucedo (reflecting their relative dispersal capacities); and (3) genetic variation will be greatest in F. sultana (reflecting a propensity for genetic divergence as a result of its low dispersal potential). We found that hydrological connectivity enhanced genetic diversity and gene flow among C. mucedo populations but not in F. sultana while higher overall measures of clonal diversity and greater genetic divergence characterized populations of F. sultana. We suggest that genetic divergence over time within F. sultana populations reflects a general constraint of releasing propagules that might eventually be swept to sea when taxa inhabit running waters. In contrast, taxa that primarily inhabit lakes and ponds may colonize across hydrologically connected regions, establishing genetically related populations. Our study contributes more nuanced views about drivers of population genetic structures in passively dispersing freshwater invertebrates as outlined by the Monopolization Hypothesis (Acta Oecologica, 23, 2002, 121) by highlighting how a range of demographic and evolutionary processes reflect life-history attributes of benthic colonial invertebrates (bryozoans) and cyclically parthenogenetic zooplankton. In addition, growing evidence that genetic divergence may commonly characterize populations of diverse groups of riverine taxa suggests that organisms inhabiting lotic systems may be particularly challenged by environmental change. Such change may predispose riverine populations to extinction as a result of genetic divergence combined with limited dispersal and gene flow.Open research badgesThis article has earned an Open Data Badge for making publicly available the digitally-shareable data necessary to reproduce the reported results. The data is available at https://doi.org/10.5061/dryad.1tm8705.

Dataset Information

?2 GABAAR Trafficking and the Consequences of Human Genetic Variation.

Publications

γ2 GABA<sub>A</sub>R Trafficking and the Consequences of Human Genetic Variation.

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