RESEARCH INTEREST

The control of inhibitory neurotransmission, with emphasis on the construction and regulation of inhibitory synapses. We are particularly interested in how neurons regulate the cell surface number and activity of the receptors for gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain.


RESEARCH TECHNIQUES

Molecular cloning and protein expression, yeast 2-hybrid screening, protein purification, analysis of protein phosphorylation and ubiquitination, antibody production, neuronal tissue culture, immunohistochemistry, confocal microscopy, live cell imaging, homologous recombination in embryonic stem cells, transgenic mouse production, and behavioural analysis.


RESEARCH SUMMARY

The interests of my laboratory centre on receptors that mediate the actions of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. GABA mediates its fast synaptic action via ionotropic chloride selective GABA_A and GABA_C receptors. The slower inhibitory actions of GABA are mediated by GABA_B receptors, which are G-protein coupled receptors. GABA receptors are also of major clinical significance as drug targets for anticonvulsant and sedative agents including: benzodiazepines, barbiturates, baclofen and some general anaesthetics. Moreover, changes in the activity of GABA receptors are critical in epilepsy and in a number of other disease states such as anxiety, substance abuse, schizophrenia, and depression. We are primarily interested in how these differing types of GABA receptors are targeted to the appropriate synaptic sites, and in dissecting the signalling pathways neurons use to modulate their activity and cell surface stability. Much of our current work centres on the control of GABA receptor activity and membrane trafficking by covalent modifications such as protein phosphorylation, ubiquitination and palmitylation. We are using homologous recombination to produce mouse lines in which the phosphorylation of individual GABA_A receptors has been ablated. This approach will allow us to precisely determine the role of protein phosphorylation in controlling the activity of GABA receptors and therefore the efficacy of synaptic inhibition, in addition to whole animal behaviour.


KEY REFERENCES

Hanley, J.G., Koulen P., Bedford F.K, Gordon-Weeks P.R. and Moss S.J. Nature 397, 66-69 (1999) Microtubule associated protein MAP-1B links GABA_C receptors to the cytoskeleton at retinal synapses.

Wang, H.W., Bedford, F.K., Brandon, N.J., Moss S.J. and Olsen R. Nature 397, 69-72 (1999). GABARAP: A putative linker Molecule between GABA_A receptors and the cytoskeleton.

Brandon, N., Uren, J., Kittler, J. T., Wang, H., Olsen R., Parker P.J. and Moss S.J.
J. Neurosci. 19, 9228-9234 (1999). Subunit specific association of protein kinase C and the receptor for activated C kinase with g -aminobutyric acid type A receptors..

Filippov, A.K., Couve, A., Pangalos, M.N., Walsh, F.S., Brown, D.A., and Moss S.J.
J. Neurosci. 20, 2867-2874 (2000). Heteromeric assembly of GABA_B R1 and R2 receptor subunits inhibit Ca+2 current in sympathetic neurones.

Kittler, J.T., Delmas P., Jovanovic, J.N., Brown, D.A., Smart T.G., and Moss S.J.
J. Neurosci 20, 7972-7977 (2000). Constitutive endocytosis of GABA_A receptors by an association with the adaptin AP2 complex modulates inhibitory synaptic currents in hippocampal neurons.

Couve, A., Moss, S.J. and Pangalos M.N. Mol. Cell Neurosci. 16, 296-312 (2000). GABA_B receptors a new paradigm in G-protein signalling.

Moss S.J. and Smart T.G. Nature Neurosci. Rev. 2, 240-250 (2001). Constructing inhibitory synapses.

Bedford F.K., Kittler, J.T., Uren, J.M., Thomas, P., Smart, T.G. and Moss S.J.
Nature Neurosci 4, 908-916 (2001). Plic-1 a ubiquitin related protein controls GABA_A receptor membrane trafficking.

Couve, A., Thomas P., Hirst W., Calver, A., Pangalos M., Walsh F.S., Smart T.G. and Moss SJ. Nat. Neurosci. 5, 415-424 (2002). A Novel role for by cAMP-dependent protein kinase phosphorylation in facilitating GABA_B effector coupling.

Brandon, N.J., Jovanovic, J., Smart T.G. and Moss S.J. J. Neurosci. 22, 6353-6361 (2002). RACK-1 facilitates PKC phosphorylation and functional modulation of GABA_A receptors upon the activation of G-protein coupled receptors.

Kittler J.T., and Moss S.J. Curr. Opin. Neurobiol. 13(3), 341-347 (2003). Modulation of GABA_A receptor activity by phosphorylation and receptor trafficking: implications for the efficacy of synaptic inhibition.