The mechanism of action and significance of RIC-3, a selective molecular chaperone for nicotinic and 5-HT3 receptors. (360G-Wellcome-085141_B_08_Z)

RIC-3 is a recently discovered selective molecular chaperone of nicotinic acetylcholine receptors (nAChRs) and 5-hydroxytryptamine type 3 receptors (5-HT3Rs). The influence of RIC-3 is illustrated most dramatically by its effect on homomeric alpha7 nAChRs. In many host cell types the alpha7 subunit fails to produce functional receptors. In some, but not all, cell lines this can be rectified by the co-expression of RIC-3. RIC-3 also modulates the functional expression level of some, but not all , heteromeric nAChR subtypes. Importantly, RIC-3 promotes the formation of homomeric 5-HT3A, but inhibits the formation of heteromeric 5-HT3AB, receptors. Accumulating evidence suggests that RIC-3 exerts these effects by modulating receptor maturation, but there is considerable uncertainty about its precise mechanism of action. We will explore the mechanisms by which RIC-3 modulates receptor maturation and function. In addition, we will generate a RIC-3-DsRed knock-in transgenic animal to enab le us to explore RIC-3 function and expression on endogenous receptors. To explore the in vivo significance of RIC-3, we will examine the phenotype of RIC-3 null mutants, using a conditional knockout approach. We will concentrate our initial characterisation on learning and memory, indicators of anxiety and schizophrenia and animals responses to nicotine.