Cellular ablation, additional deg-1 alleles, and careful behavioral analyses are needed to reconcile the loss of ASH mechanotransduction currents observed in this study with normal nose-touch responses previously reported for u443 animals ( Savage et al., 1994). Adjacent neurons are likely to suffice for nose-touch avoidance in deg-1 mutants ( Chatzigeorgiou and Schafer, 2011). Alternatively, deg-1-independent transduction currents might initiate ASH-mediated behavioral responses. ASH’s deg-1-independent transduction currents warrant Forskolin purchase further scrutiny. The authors speculate that these genetically distinct conductances work in parallel based

on their similar activation latencies. Alternatively, deg-1-independent currents http://www.selleckchem.com/products/BKM-120.html could be carried by force-gated channels acting upstream of deg-1. Is this current mediated by distinct DEG/ENaCs, TRP channels, or by unrelated proteins? New candidates include Piezo proteins, which are required for mechanically evoked currents in some somatosensory neurons in vitro and confer touch sensitivity in heterologous cells ( Coste et al., 2010). As with all seminal discoveries,

the findings of Geffeney and colleagues (2011) lead to more open questions. First, how are DEG/ENaC mechanotransduction channels gated? Because response latencies of <1 ms are observed in many mechanosensory cells, transduction Rutecarpine channels are thought to be force gated (Arnadóttir and Chalfie, 2010). The latency of ASH mechanotransduction currents was estimated at ∼2 ms, which the authors argue is too fast to involve chemical messengers (Geffeney et al., 2011). Additional biophysical analysis is needed to test this model. Second, how are transduction channels tuned to specific force ranges in different neurons? Native MEC-4/MEC-10 complexes in body-touch neurons are activated by submicronewton forces, substantially lower than those eliciting ASH’s DEG-1-mediated

currents (∼11 μN) or responses in other harsh-touch neurons (>100 μN; Geffeney et al., 2011 and Li et al., 2011). Intrinsic structural properties or extrinsic factors, including extracellular modifications, cytoskeletal scaffolds, and membrane environment, might govern mechanosensitivity (Arnadóttir and Chalfie, 2010). Chimeric analysis has the potential to identify important structural motifs; however, in heterologous cells, MEC-4/MEC-10 complexes are not force gated and DEG-1 does not form functional channels (Arnadóttir and Chalfie, 2010 and Wang et al., 2008). Identification of accessory proteins and in vivo analysis of engineered channels are needed to nail down gating mechanisms. Third, how are DEG/ENaCs and TRP channels functionally linked? Since OSM-9 activity is required for behavioral responses, ASH provides an excellent model to identify pathways connecting DEG-1 currents to OSM-9/OCR-2 channels.