Abstract
GABAA receptors are located on the majority of neurons in the central and peripheral nervous system, where they mediate important actions of the neurotransmitter gamma-aminobutyric acid. Early in development the trophic properties of GABA allow a healthy development of the nervous system. Most neurons have a high intracellular Cl-concentration early in life due to the late functional expression of the Cl-pump KCC2, therefore GABA has excitatory effects at this stage. Upon higher expression and activation of KCC2 GABA takes on its inhibitory effects while glutamate functions as the major excitatory neurotransmitter. Like all multisubunit membrane proteins the GABAA receptor is assembled in the ER and travels through the Golgi and remaining secretory pathway to the cell surface, where it mediates GABA actions either directly at the synapses or at extrasynaptic sites responding to ambient GABA to provide a basal tonic inhibitory state. In order to adapt to changing needs and information states, the GABAergic system is highly dynamic. That includes subtype specific trafficking to different locations in the cell, regulation of mobility by interaction with scaffold molecules, posttranslational modifications, that either directly affect channel function or the interaction with other proteins and finally the dynamic exchange between surface and intracellular receptor pools, that either prepare receptors for recycling to the surface or degradation. Here we give an overview of the current understanding of GABAA receptor functional and molecular dynamics that play a major part in maintaining the balance between excitation and inhibition and in changes in network activity.
Highlights
Healthy brain function depends on a precise regulation of neuronal activity
Protein phosphatase 1alpha (PP1A) regulates the phosphorylation of GABA receptor beta subunits through protein kinase (PKA)
GABARAP is mainly localized in intracellular compartments, such as endoplasmatic reticulum, Golgi structures and intracellular vesicles near the synapses, but only a small fraction is directly colocalized with synaptic GABA receptors
Summary
Healthy brain function depends on a precise regulation of neuronal activity. While signalling is initiated by excitatory neurotransmitters, mostly glutamate, the inhibitory neurotransmitters (glycine and GABA) prevent the system from overreacting by damping postsynaptic depolarization that leads to a reduced likelihood of the initiation of action potentials. Receptor gamma2 subunit knock out mice the synaptic gephyrin clusters are absent and the remaining alpha-beta containing receptors are diffusely distributed on the cell surface (Craig et al, 1996; Essrich et al, 1998; Günther et al, 1995). Alldred et al (2005) showed, that in gamma2 deficient neurons only transfection with exogenous gamma2, but not alpha2 rescues synaptic clustering of GABAA receptors, the recruitment of gephyrin and normal amplitude and frequency of mIPSCs. They identified the fourth transmembrane region of the gamma2 subunit as the essential domain to mediate the effects.
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