Voltage-gated potassium channel proteins and stereoselective S-nitroso-l-cysteine signaling.

S-nitroso-l-cysteine (L-CSNO) behaves as a ligand. Its soluble guanylate cyclase-independent (sGC-independent) effects are stereoselective - that is, not recapitulated by S-nitroso-d-cysteine (D-CSNO) - and are inhibited by chemical congeners. However, candidate L-CSNO receptors have not been identified. Here, we have used 2 complementary affinity chromatography assays - followed by unbiased proteomic analysis - to identify voltage-gated K+ channel (Kv) proteins as binding partners for L-CSNO. Stereoselective L-CSNO-Kv interaction was confirmed structurally and functionally using surface plasmon resonance spectroscopy; hydrogen deuterium exchange; and, in Kv1.1/Kv1.2/Kvß2-overexpressing cells, patch clamp assays. Remarkably, these sGC-independent L-CSNO effects did not involve S-nitrosylation of Kv proteins. In isolated rat and mouse respiratory control (petrosyl) ganglia, L-CSNO stereoselectively inhibited Kv channel function. Genetic ablation of Kv1.1 prevented this effect. In intact animals, L-CSNO injection at the level of the carotid body dramatically and stereoselectively increased minute ventilation while having no effect on blood pressure; this effect was inhibited by the L-CSNO congener S-methyl-l-cysteine. Kv proteins are physiologically relevant targets of endogenous L-CSNO. This may be a signaling pathway of broad relevance.

Consuming Genistein Improves Survival Rates in the Absence of Laxative in ΔF508-CF Female Mice.

Genistein is a naturally occurring isoflavone found in soy. Genistein has been shown to increase the open probability of the most common cystic fibrosis (CF) disease-associated mutation, ∆F508-CFTR. Mice homozygous for the ∆F508 mutation are characterized with severe intestinal disease and require constant laxative treatment for survival. This pathology mimics the intestinal obstruction (meconium ileus) seen in some cystic fibrosis patients. This study tested whether dietary supplementation with genistein would reduce the dependence of the ∆F508 CF mouse model on laxatives for survival, thereby improving mortality rates. At weaning (21 days), homozygous ∆F508 mice were maintained on one of three diet regimens for a period of up to 65 days: normal diet, normal diet plus colyte, or genistein diet. Survival rates for males were as follows: standard diet (38%, n = 21), standard diet plus colyte (83%, n = 42) and genistein diet (60%, n = 15). Survival rates for females were as follows: standard diet (47%, n = 19), standard diet plus colyte (71%, n = 38), and genistein diet (87%, n = 15). Average weight of male mice fed genistein diet increased by ~2.5 g more (p = 0.006) compared to those with colyte treatment. Genistein diet did not change final body weight of females. Expression of intestinal SGLT-1 increased 2-fold (p = 0.0005) with genistein diet in females (no change in males, p = 0.722). Expression of GLUT2 and GLUT5 was comparable between all diet groups. Genistein diet reduced the number of goblet cells per micrometer of crypt depth in female (p = 0.0483), yet was without effect in males (p = 0.7267). The results from this study demonstrate that supplementation of diet with genistein for ~45 days increases the survival rate of female ∆F508-CF mice (precluding the requirement for laxatives), and genistein only improves weight gain in males.

headspace: National Youth Mental Health Foundation: making headway with rural young people and their mental health.

Mental health is the number one health issue affecting young people in Australia today, yet only one in four of these young people receive professional help. Approximately 14% of 12- to 17-year-olds and 27% of 18- to 25-year-olds experience mental health problems each year. However, many do not have ready access to treatment or are reluctant to seek that help. These issues might be exacerbated in the rural and remote regions of Australia where sociocultural barriers such as stigma, lack of anonymity and logistic difficulties including cost and availability of transport can hinder young people accessing mental health services. headspace: the National Youth Mental Health Foundation has been funded to address these issues. headspace will provide funding for the establishment of communities of youth services across Australia, provide national and local community awareness campaigns and plans, establish a centre of excellence that will identify and disseminate evidence-based practice in addressing youth mental health issues, and translate findings into education and training programs that are targeted at service providers to work with youth mental health. The communities of youth services will build the capacity of local communities to identify early, and provide effective responses to, young people aged 12-25 years with mental health and related substance use disorders. Specific approaches in rural, regional and remote areas will be developed as well as specific programs to involve young Indigenous people.