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Biological and therapeutic roles of GlyRs containing the alpha2 and alpha3 subunits
Using subunit-specific antibodies and knockout mice, we have uncovered key biological roles of these 'minor' GlyR isoforms. For example, GlyRs containing the α3 subunit are highly expressed in the dorsal horn of the spinal cord and several brainstem nuclei. This information led to the discovery that α3 subunit knockout mice are defective in prostaglandin (PGE2)-mediated inflammatory pain sensitisation (Harvey et al 2004, Science 304: 884-887) and rhythmic breathing (Manzke et al 2010, J Clin Invest 120: 4118-4128). More recently, in collaboration with Laurent Nguyen and Jean-Michel Rigo (Hasselt University, Belgium) GlyRs containing the α2 subunit have been shown play a key role in migration of cortical interneurons (Avila et al 2013, Cell Reports 4:738-750; Avila et al 2014, Cell Death Differ 21:1696-1708). We are also examining the functions of the expanded GlyR gene family in zebrafish (α1, α2, α3, α4a, α4b, βa and βb), revealing new movement phenotypes and new mutants with defective glycinergic transmission (Ganser et al 2013, Neurobiol Dis 60:139-151; Hirata et al 2013, J Neurosci 33:14638-14634). Future research aims to: i) Characterise additional phenotypes in GlyR α2 and α3 knockout mice at the molecular and behavioural level; ii) To develop modulators of GlyR α3 function as novel therapeutics for inflammatory pain or breathing disorders. Key collaborators include: Julia Dallman (University of Miami, USA), Hiromi Hirata (Graduate School of Science and Engineering, Aoyama Gakuin University, Sagamihara, Japan), Trevor Smart (UCL NPP).
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