, 2003, Lechner et al., 2009, Lee et al., 2003, Naylor et al., 2010, Nealen et al., 2003, Oberwinkler et al., 2005, Oberwinkler and

Philipp, 2007, selleck chemical Staaf et al., 2010 and Wagner et al., 2008). Reported in vitro TRPM3-activating stimuli included hypotonic cell swelling, internal Ca2+ store depletion, D-erythro-sphingosine, and PS ( Grimm et al., 2003, Grimm et al., 2005, Lee et al., 2003 and Wagner et al., 2008). With the use of PS, which is currently the most potent and selective available pharmacological tool to probe for biological roles of TRPM3 ( Wagner et al., 2008), evidence has been provided suggesting functional expression of the channel in pancreatic beta cells and vascular smooth muscle ( Naylor et al., 2010 and Wagner et al., 2008). However, the actual stimuli that regulate TRPM3 activity in vivo and the physiological roles of TRPM3 remained largely unknown. In this work, we provide the first description of Linsitinib Trpm3−/− mice, which will form a firm basis for further investigation of the biological roles of TRPM3. Trpm3−/− mice exhibited no obvious deficits in fertility, gross anatomy, body weight, core body temperature, locomotion, or exploratory behavior. With respect to the proposed role of TRPM3 in

insulin release, we also did not find differences in resting blood glucose, suggesting that basal glucose homeostasis is not critically affected. Thus, Trpm3−/− mice

appear generally healthy, with no indications of major developmental or metabolic deficits. In addition, several behavioral aspects related to somatosensation and nociception were unaltered in the Trpm3−/− mice, including the avoidance of cold temperatures and the nocifensive response to mechanical stimuli or capsaicin injections. We found, however, significant and specific deficits in the nocifensive responses to TRPM3-activating stimuli. First, we confirmed and further substantiated an earlier study showing that injection either of PS elicits pain in mice ( Ueda et al., 2001). Intraplantar injection of PS in Trpm3+/+ mice induced a strong nocifensive response, consisting of vigorous licking and lifting of the hindpaw, which was comparable to what we observed upon injection of the TRPV1 agonist capsaicin. This pain response was conserved in Trpv1−/−/Trpa1−/− double-knockout mice but fully abrogated in Trpm3−/− mice, indicating that TRPM3 is the main PS sensor in nociceptors. Similarly, we found that addition of PS to the drinking water led to a moderate reduction of water consumption in Trpm3+/+ but not in Trpm3−/− mice, indicative of TRPM3-dependent PS aversion.