Although there is evidence that Clic genes encode intracellular chloride channels (Ashley, 2003), this channel activity is somewhat controversial and several other functions have been suggested. Vertebrate CLIC4 or other CLIC proteins bind and likely regulate the function of ryanodine receptors (Jalilian et al., 2008), 14-3-3 proteins (Suginta et al., 2001) and A-kinase anchoring proteins (Shanks et al., 2002) Additionally, CLIC4 interacts with Smad proteins and is consequently a mediator of TGF-β or bone morphogenic protein (BMP) signaling (Shukla et al., 2009). The relevance of these biochemical functions for CLIC4 or other CLIC proteins in behavioral responses to ethanol is unknown currently. Our bioinformatics studies on gene networks associated with Clic4 basal expression in mouse PFC (Supplementary Figure S7), however, provide correlative evidence that Clic4 might modulate RNA processing and trafficking. This possibility is particularly interesting since CLIC4 is a mediator of TGF-β signaling and this pathway is known to modulate RNA processing via Smad protein interaction with RNA binding sites on miRNA (Davis et al., 2008). Thus, CLIC4 might regulate TGF-β/Smad-mediated modulation of RNA processing and therefore protein expression,
