, 2008). Interestingly, certain stargazin polymorphisms were shown to be associated with enhanced responsiveness to lithium, a

common treatment for bipolar disorder (Silberberg et al., 2008). Finally, polymorphisms in human stargazin have been linked to susceptibility to chronic pain in a subset of cancer patients (Nissenbaum et al., 2010). These human genetic and histological data are complex, and in some cases contradictory, but when taken together, point to a plausible link between TARPs and the pathophysiology of several neurological and psychiatric disorders. TARPs may therefore serve as novel pharmacological targets and/or markers for a variety of human diseases. As the role of TARPs

in mammalian systems was being worked out, Maricq and colleagues identified NVP-BKM120 cost an unrelated auxiliary selleck products subunit for GLR-1, the AMPAR homolog in C. elegans, using an elegant genetic screen ( Zheng et al., 2004). In brief, they made a transgenic worm expressing a GLR-1 subunit containing the same mutation that occurs in lurcher mutant mice. This results in a constitutively active GLR-1, a gain-of-function mutation that causes a marked “hyper-reversal” movement phenotype. They then screened for mutations that suppressed this behavior and identified suppressor of lurcher (sol-1). SOL-1 is predicted to be a type 1 transmembrane protein with a single transmembrane domain and four extracellular N-terminal complement subcomponents (C1r/C1s), urchin embryonic growth factor (Uegf), and bone morphogenetic protein (Bmp1), comprising CUB (C1r/C1s/Uegf/Bmp1) domains ( Figures 2B and 2C). CUB domains are conserved, developmentally regulated, structural modules present in the extracellular domains of a diverse set of

membrane proteins ( Bork and Beckmann, 1993). SOL-1 colocalizes with GLR-1 at synaptic puncta, but is not necessary for the surface expression of GLR-1. Coimmunoprecipitation studies in COS-7 cells show that antibodies to SOL-1 coprecipitate GLR-1. Despite the seemingly normal synaptic targeting of GLR-1 in the absence of SOL-1, electrophysiological recordings from neurons expressing GLR-1 demonstrate Calpain that SOL-1 is essential for GLR-1 function. On the other hand, NMDAR function remains intact. Further studies indicate that SOL-1 controls the gating of GLR-1 and that the extracellular CUB domain 3 is required for this action ( Zheng et al., 2006). Interestingly, and in striking contrast to vertebrate AMPARs, expression of GLR-1 in heterologous cells fails to elicit currents, indicating that a functional GLR-1 requires one or more additional proteins. Surprisingly, expression of SOL-1 together with GLR-1 in heterologous cells also fails to restore GLR-1 function.