Modulation of GABAA receptor activity by phosphorylation and receptor trafficking: implications for the efficacy of synaptic inhibition
Introduction
Ionotropic γ-aminobutyric acid type A (GABAA) receptors mediate the majority of fast inhibitory synaptic transmission in the brain, in addition to being drug targets for benzodiazepines, barbiturates, neurosteroids and some anesthetics. Moreover, modifications in GABAA receptor function are crucial in some forms of epilepsy, and are strongly implicated in anxiety, depression and chronic substance abuse. GABAA receptors play a key role in controlling neuronal activity, and therefore modulating their function will have important consequences for neuronal excitation. One accepted means of modifying the efficacy of synaptic transmission when under conditions of neurotransmitter saturation is to change the number and/or sensitivity of postsynaptic receptors. Here, we analyze the mechanisms that modulate the number and activity of GABAA receptors at inhibitory synapses and their implications in controlling neuronal excitability.
Section snippets
GABAA receptor structure
GABAA receptors are pentameric hetero-oligomers, the subunits of which share a conserved structure that consists of a large extracellular amino-terminal, four transmembrane (TM) domains and a large intracellular loop between TM domains III and IV [1]. Sixteen distinct GABAA receptor subunit genes have been identified to date, which are classified by sequence identity into seven subunit classes: α1-6, β1-3, γ1-3, δ, ε, π and θ [2]. The differing spatial and temporal patterns of subunit gene
The incorporation and stability of GABAA receptors at inhibitory synapses: role of associated proteins
GABAA receptor assembly occurs within the endoplasmic reticulum (ER) (for example see 1., 4., 5.), and it is crucial for efficient inhibitory neurotransmission that correctly assembled receptors are transported to, and inserted at the appropriate postsynaptic sites (Figure 1). How this synaptic targeting is achieved is poorly understood, but it is believed to be dependent on the GABAA receptor γ2 subunit and the multifunctional protein gephyrin. Evidence for a crucial role of the γ2 subunit in
Dynamic regulation of GABAA receptor number at inhibitory synapses
Another factor that is important for regulating the efficacy of GABAergic inhibition is the stability of GABAA receptors at synapses. For some inhibitory synapses, a direct relationship between the number of synaptic GABAA receptors and the strength of the synapse has been demonstrated 27., 28.. Therefore, modulating the insertion or removal rate of GABAA receptors into or from the membrane could have a marked effect on the amplitude of inhibitory synaptic currents [29]. Evidence exists that
GABAA receptor functional modulation: the role of phosphorylation
The endogenous mechanisms that neurons use to control the activity and subcellular distribution of GABAA receptors remain to be elucidated, however, direct phosphorylation has been suggested to be of major importance. The most compelling evidence for this comes from the study of recombinant receptors (reviewed in [35]). These approaches have demonstrated that GABAA receptor function, dependent upon the subtype analyzed, can be differentially modulated by phosphorylation of key residues within
Concluding remarks and future directions
It is apparent that GABAA receptors at inhibitory synapses are dynamic entities, whose number and activity can be modified by both direct phosphorylation and membrane trafficking. A crucial future goal will be to determine if changes in the levels of receptor phosphorylation underlie some of the previously reported forms of activity-dependent GABAergic plasticity [49•], and/or the effects of BDNF on receptor activity and inhibitory synapse formation 31., 41., 50.. Similarly, it will be
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
This work was supported by the Medical Research Council and the Wellcome Trust.
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