Biological and therapeutic roles of glycine receptors containing the alpha2 or alpha3 subunits

The central nervous system (CNS) is a complex, intricate network of nerve cells (neurones) whose primary function is to transmit and receive messages. This communication occurs at specialised sites of contact known as synapses. At these sites, an arriving nerve impulse causes the release of a chemical (neurotransmitter) which then interacts with receptor molecules embedded in the cell membrane of a neighbouring neurone. Some types of these receptors (e.g. glycine receptors) possess specific ion-permeable channels. The opening of these channels in response to neurotransmitter alters the electrical state of the cell either transmitting or subtly altering the incoming nerve impulse. The molecular mechanisms that regulate synaptic transmission and nerve impulse activity are important in understanding normal and diseased states of the brain. Indeed, many major drugs act primarily via receptor/ion channels. The therapeutic nature of these agents provides a compelling reason for further understanding the molecular details of the structure and function of this receptor class.

This proposal will benefit research in this area by enhancing our knowledge concerning glycine receptors, inhibitory ion channels found mainly in the spinal cord and brainstem. Animal models and human studies of glycine receptors have shown that one receptor subtype (called alpha1) is involved in a rare neurological disorder (startle disease). By creating a knockout mouse where the gene for another subtype (alpha3) was disrupted, we found that this was important in inflammatory pain. New therapeutic targets for inflammatory and chronic pain are a current clinical need given that the long-term use of classical analgesics is hampered by severe side effects such as gastric ulcerations leading to significant mortality in the elderly or, for the COX2 inhibitors, a predisposition to heart attacks and stroke. Our major aims are: i) to characterise molecular variants and locations of the alpha2 and alpha3 GlyRs in the CNS; ii) to assess the contribution of the glycine receptor alpha3 subunit to inflammatory and chronic pain; iii) to discover drugs might positively modulate glycine receptors containing the alpha1 versus alpha3 subunits, the first step in developing new treatments for pain; iv) to discover the role of the alpha2 subtype by creating a knockout mouse which will lack these receptors. Taken together, our studies will inform the development of new therapeutic treatments for inflammatory and/or chronic pain and may uncover human disorders involving defects in the alpha2 subunit gene.

We have recently revealed a new important role for inhibitory glycine receptors (GlyRs) containing the alpha3 subunit in prostaglandin-mediated inflammatory pain sensitisation (see Harvey et al., 2004, Science 304:884-887). This programme aims to: i) assess RNA editing and sites of expression of alpha2 and alpha3 subunit GlyRs; ii) examine the role of GlyR alpha3 in models of neuropathic pain; iii) study allosteric modulation of GlyRs by existing and novel compounds with potential therapeutic implications; and iv) generate a knockout model for the alpha2 GlyR subtype, which has been implicated in the formation of glycinergic synapses, cortical differentiation and rod photoreceptor development. This study will bring together molecular, behavioural, electrophysiological and gene knockout expertise to define the emerging biological and potential therapeutic roles of glycine receptors.