Alcohol is the most commonly abused drug worldwide, and chronic alcohol consumption is a major etiological factor in the development of multiple pathological sequelae, including alcoholic cardiomyopathy and hepatic cirrhosis. Here, we identify regulator of G protein signaling 6 (RGS6) as a critical regulator of both alcohol-seeking behaviors and the associated cardiac and hepatic morbidities through two mechanistically divergent signaling actions. RGS6−/− mice consume less alcohol when given free access and are less susceptible to alcohol-induced reward and withdrawal. Antagonism of GABAB receptors or dopamine D2 receptors partially reversed the reduction in alcohol consumption in RGS6−/− animals. Strikingly, dopamine transporter inhibition completely restored alcohol seeking in mice lacking RGS6. RGS6 deficiency was associated with alterations in the expression of genes controlling dopamine (DA) homeostasis and a reduction in DA levels in the striatum. Taken together, these data implicate RGS6 as an essential regulator of DA bioavailability. RGS6 deficiency also provided dramatic protection against cardiac hypertrophy and fibrosis, hepatic steatosis, and gastrointestinal barrier dysfunction and endotoxemia when mice were forced to consume alcohol. Although RGS proteins canonically function as G-protein regulators, RGS6-dependent, alcohol-mediated toxicity in the heart, liver, and gastrointestinal tract involves the ability of RGS6 to promote reactive oxygen species-dependent apoptosis, an action independent of its G-protein regulatory capacity. We propose that inhibition of RGS6 might represent a viable means to reduce alcohol cravings and withdrawal in human patients, while simultaneously protecting the heart and liver from further damage upon relapse.

Urinary bladder cancer, the fifth most common cancer in the United States, is largely caused by exposure to toxic chemicals including those from smoking. Polymorphisms in the RGS6 gene leading to increased RGS6 translation are associated with a pronounced reduction in the risk of bladder cancer, especially among smokers. We employed a RGS6‐/‐ mouse line to interrogate the role of RGS6 in BBN‐induced bladder carcinogenesis, a model that closely resembles human invasive bladder cancer. RGS6 is highly expressed in mouse bladders, including urothelium where transitional cell carcinoma originates. Ablation of RGS6 greatly shortened the time needed for BBN‐induced bladder tumor formation (12 wks vs 20 wks in wild type (WT) mice). Consistently, WT mice treated with BBN showed a marked down‐regulation of RGS6 and Gβ5 as well as a transient activation of p53 (phosphorylation of S15), the latter of which was greatly blunted in RGS6‐/‐ mice. Loss of RGS6, either in BBN‐treated WT mice or RGS6‐/‐ mice, also resulted in an increase in DNMT1 in bladder urothelium, consistent with our recent evidence that RGS6 functions as a scaffold to promote DNMT1 degradation. Consequently, expression of tumor suppressor RASSF1A, a direct downstream target of DNMT1, was greatly repressed in RGS6‐/‐ urothelium. Our findings show that RGS6 is a previously unrecognized, but critical repressor of bladder carcinogenesis. Loss of RGS6, observed during BBN‐induced mouse bladder carcinogenesis and in human bladder tumors, would be expected to drive carcinogenesis through impaired p53 activation and increased expression of DNMT1. (Supported by AHA 11SDG7580008 (JY) and NIH CA161882 (RAF))