The synaptic targeting and regulation of inhibitory amino acid neurotransmitter receptors

Professor Stephen J. Moss
Professor of Molecular Pharmacology and Cell Biology

Current address:

Tufts University Department of Neuroscience

136 Harrison Ave – Arnold 207

Boston, MA 02111 USA

Tel: +00 617-636 3976

Research assistants at UCL:

  • Mike Lumb

Professor Stephen J. Moss graduated in Biochemistry (University of Bath) in 1984 and received a PhD in Molecular Neurobiology (University of Cambridge) in 1989. Between 1989-1992, he took a Postdoctoral Fellowship at Howard Hughes Medical Institute, Dept of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, USA and, between 1992-1993, a Postdoctoral Fellowship in the UCL Department of Biology. In 1993, he was appointed Lecturer in Pharmacology and group leader in the UCL Laboratory for Molecular Cell Biology. In October 2000 Stephen became Professor in Molecular Pharmacology and Cell Biology. In 2003 he took up an appointment as Professor at in the Department of Neuroscience at the University of Pennsylvania, USA and in 2008 moved on to become Professor and Associate Director of Corporate Alliances at Tufts University, Boston, USA; however, he still retains his joint appointment here at UCL.

Research in the Moss lab focuses on the receptors that mediate the actions of γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the vertebrate nervous system. GABA receptors are also critical drug targets for anticonvulsants, sedatives and anesthetics. We are interested in understanding how neurons regulate the accumulation of these critical inhibitory receptors on the neuronal surface in addition to their functional properties. Given that altered GABAA receptor function plays critical roles in a number of neuropsychiatric disorders the results may lead to new insights and therapeutic strategies for such debilitating disorders as epilepsy, anxiety, schizophrenia, depression and substance abuse.

Research Interests

The fast inhibitory (milliseconds) action of GABA in the mammalian brain is largely mediated by GABAA receptors, which are chloride selective ligand-gated ion channels. Their activation in adult brain results in neuronal hyperpolarization.GABAA receptors are also the sites of action for benzodiazepines, barbiturates, neurosteroids and general anesthetics, which all act to potentiate receptor activity together and affect the efficacy of inhibitory synaptic transmission. Compromised GABAΑ receptor function is significant in a number of CNS disorders including: epilepsy, anxiety, sleep disorders, addiction, autism and mental retardation.

The slow inhibitory actions (seconds to minutes) of GABA are mediated by GABAB receptors which are G-protein coupled receptors (GPCRs). Postsynaptically GABAB receptors activate inwardly-rectifying K+ channels leading to neuronal hyper-polarization while presynaptically they inactivate voltage-gated Ca2+ channels, decreasing neurotransmitter release. GABAB receptors also inhibit adenylate cyclase leading to diminished activity of PKA signaling pathways. Compromised GABAB receptor function is significant in epilepsy and has been strongly implicated in depression, neuropathic pain, addiction and feeding behavior.

Given the critical role that GABA receptors play in synaptic inhibition, as drug targets and in human pathology it is of fundamental importance to understand how neurons regulate their accumulation on the surface of neurons and their functional properties. To address these issues we use a combination of biochemical, cell biological, electrophysiological, genetic and pharmacological experimental approaches to detail these endogenous mechanisms for GABAA and GABAB receptors respectively.

GABAA Receptors

Molecular and biochemical studies have revealed that GABAΑ receptors are pentameric hetero-oligomers that can be assembled from 7 subunit classes: α(1-6), β(1-3), γ(1-3), δ, ε, θ and π. However, in vivo the majority of synaptic benzodiazepine-sensitive GABAΑ receptor subtypes are composed of α, β and γ2 subunits. Receptors composed of αβ or αβδ subunits are believed to form extrasynaptic receptors that mediate tonic inhibition but are insensitive to functional modulation by classic benzodiazepines.


We are principally interested in understanding how neurons regulate the accumulation of GABAA receptors at the appropriate subcellular specialization. We also study the endogenous mechanisms neurons use to control GABAA receptor functional expression with particular emphasis on the roles played by post-translational modifications of receptor structure such as phosphorylation and ubiquitination. To address these issue we combine molecular, imaging, biochemical, genetic, electrophysiological and pharmacological approaches.

Our studies have revealed that GABAA receptors are dynamic entities on the cell surface of neurons that undergo rapid rates of constitutive clathrin-mediated endocytosis and recycling, processes that determine the cell surface number of GABAA receptors, together with the efficacy of synaptic inhibition. Moreover the “membrane trafficking” of GABAA receptors is subject to dynamic modulation by receptor phosphorylation and via their interaction with specific receptor associated proteins (Kittler and Moss, 2003).

With regard to phosphorylation it is evident that GABAA receptors are phosphorylated in neurons and that this process is subject to dynamic modulation by metabotropic neurotransmitters and growth factor receptors that modify the activity of protein kinases and phosphatases (Brandon et al., 2002; Jovanovic et al., 2004; Kittler et al., 2005; Chen et al., 2006). Modified phosphorylation in turn regulates the binding of GABAA receptors to the AP2 adaptin, a critical regulator of GABAA receptor endocytosis.


Recently we have demonstrated that GABAA receptor endocytic sorting, is regulated by direct binding to Huntingtin-associated protein (HAP1; Kittler et al., 2004). In addition it is also evident that receptor insertion at the plasma membrane is regulated via interaction with 2 other distinct receptor associated proteins GABAARAP and Plic-1 respectively (Kittler and Moss, 2003). In addition using RNAi and live imaging we have established that the inhibitory postsynaptic scaffold protein gephyrin regulates GABAA receptor lateral mobility, promoting the accumulation of these receptors at inhibitory synapses (Jacob et al., 2005).


Currently we are utilizing homologous recombination to make mouse lines in which the phosphorylation of individual subunits or their ability to bind specific receptor associated proteins has been abolished. These animals will allow us to ascertain the role that these putative regulatory mechanisms play in the control of synaptic inhibition and animal behavior in addition to pathological conditions such as epilepsy.

GABAB Receptors

In contrast to the majority of other G-protein coupled receptors (GPCRs), the formation of functional GABAB receptors is dependent upon the assembly of functional heterodimers composed of GABABR1 and R2 subunits (Couve et al., 2004). Given the unique structure of GABAB receptors we are currently examining the cellular mechanisms neurons use to control the function of these atypical GPCRs.

Our results have revealed that GABAB receptors, in contrast to the monomeric GPCRs as typified by studies on the β-adrenergic receptor, undergo agonist-induced phosphorylation and desensitization and consequently exhibit half-lives of approximately 30h on the surface of neurons (Fairfax et al., 2004; Couve et al., 2004). It is also evident that direct phosphorylation of GABAB receptors within the cytoplasmic tail of the GABAB R2 subunit by cAMP-dependent, or AMP-dependent protein kinases is a powerful modulator of their functional coupling to effectors such as K+ channels. However, in contrast to monomeric GPCRs direct phosphorylation by these kinases reduces GABAB receptor desensitization promoting their functional coupling (Couve et al., 2002; 2004).


To address the significance of this novel mode of GPCR regulation we are studying GABAB receptor function in mice in which specific sites of phosphorylation with either the receptor R1 and R2 subunits have been mutated.

Link to current website at Tufts

Selected Publications