Clustering and Synaptic Targeting of GABA-A Receptors

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant):
The long-term goal of our research is to unravel the mechanism regulating the
clustering and postsynaptic targeting of g-aminobutyric acid type A (GABAA)
receptors. These receptors are hetero-pentameric chloride channels and they
mediate most inhibitory neurotransmission in the brain. GABAA receptor subtypes
distinguished by their subunit composition are differentially expressed at the
regional and cellular level. Differential localization of GABAA receptors is
implicated in regulation of synaptic efficacy of GABAergic transmission and
pathological changes in receptor localization are implicated in debilitating
disorders such as epilepsy and anxiety. The factors and signaling pathways that
determine receptor clustering and localization are largely unknown and shall be
identified as part of this proposal. Most GABAA receptor subtypes are clustered
at postsynaptic sites by a mechanism that requires the g2 subunit and the
clustering protein gephyrin. Different a subunits might target receptors to
different types of synapses. However, it is not known how GABAA receptors are
linked to gephyrin and to the subsynaptic cytoskeleton. We hypothesize that
synaptic localization is mediated at least in part by postsynaptic proteins
that interact with cytoplasmic protein domains of the g2 subunit. To test this
hypothesis we will map g2 subunit domains that mediate postsynaptic
localization in neurons. Loss of the g2 subunit in vivo is associated with a
reduced GABAA receptor channel conductance. It has been postulated that this
reduced channel function during neural development might contribute to loss of
GABAA receptor clusters in g2 subunit deficient neurons. Genetic approaches
will be used to determine whether receptor activation is required for
clustering of GABAA receptors. Finally, novel GABAA receptor binding proteins
that interact with the g2 or a2 subunits will be analyzed with respect to their
role in receptor clustering and localization. These studies will significantly
advance our understanding of the regulation of GABAergic neurotransmission and
identify new potential drug targets for the treatment of mental and
neurological disorders such as anxiety and epilepsy.
StatusFinished
Effective start/end date8/1/027/31/03

Funding

  • National Institute of Mental Health: $310,241.00

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