Trafficking and signaling of G protein-coupled receptors in the nervous system: implications for disease and therapy

G protein-coupled receptors (GPCRs) are expressed throughout the nervous system where they regulate multiple physiological processes, participate in neurological diseases, and are major targets for therapy. Given that many GPCRs respond to neurotransmitters and hormones that are present in the extracellular fluid and which do not readily cross the plasma membrane, receptor trafficking to and from the plasma membrane is a critically important determinant of cellular responsiveness. Moreover, trafficking of GPCRs throughout the endosomal system can initiate signaling events that are mechanistically and functionally distinct from those operating at the plasma membrane. This review discusses recent advances in the relationship between signaling and trafficking of GPCRs in the nervous system. It summarizes how receptor modifications influence trafficking, discusses mechanisms that regulate GPCR trafficking to and from the plasma membrane, reviews the relationship between trafficking and signaling, and considers the implications of GPCR trafficking to drug development.

When we eat, which bacteria should we be feeding?

Diet therapy utilizing probiotics and prebiotics may help treat many common gastrointestinal complaints. From birth to about 2 years of age the human digestive tract changes from sterile to a complex ecosystem with at least 500 bacterial species, most of these are benign and even necessary, however, pathogenic species also colonize the digestive tract. The idea is that prebiotics and probiotics can be used to displace and neutralise these pathogens.

Gut permeability in autism spectrum disorders

Objective To test whether gut permeability is increased in autism spectrum disorders (ASD) by evaluating gut permeability in a population-derived cohort of children with ASD compared with age- and intelligence quotient-matched controls without ASD but with special educational needs (SEN). Patients and Methods One hundred thirty-three children aged 10–14 years, 103 with ASD and 30 with SEN, were given an oral test dose of mannitol and lactulose and urine collected for 6 hr. Gut permeability was assessed by measuring the urine lactulose/mannitol (L/M) recovery ratio by electrospray mass spectrometry-mass spectrometry. The ASD group was subcategorized for comparison into those without (n = 83) and with (n = 20) regression. Results There was no significant difference in L/M recovery ratio (mean (95% confidence interval)) between the groups with ASD: 0.015 (0.013–0.018), and SEN: 0.014 (0.009–0.019), nor in lactulose, mannitol, or creatinine recovery. No significant differences were observed in any parameter for the regressed versus non-regressed ASD groups. Results were consistent with previously published normal ranges. Eleven children (9/103 = 8.7% ASD and 2/30 = 6.7% SEN) had L/M recovery ratio > 0.03 (the accepted normal range cut-off), of whom two (one ASD and one SEN) had more definitely pathological L/M recovery ratios > 0.04. Conclusion There is no statistically significant group difference in small intestine permeability in a population cohort-derived group of children with ASD compared with a control group with SEN. Of the two children (one ASD and one SEN) with an L/M recovery ratio of > 0.04, one had undiagnosed asymptomatic celiac disease (ASD) and the other (SEN) past extensive surgery for gastroschisis.

British Nutrition Foundation annual lecture: chips with everything? Nutritional genomics and the application of diet in disease prevention

The development of high throughput techniques ('chip' technology) for measurement of gene expression and gene polymorphisms (genomics), and techniques for measuring global protein expression (proteomics) and metabolite profile (metabolomics) are revolutionising life science research, including research in human nutrition. In particular, the ability to undertake large-scale genotyping and to identify gene polymorphisms that determine risk of chronic disease (candidate genes) could enable definition of an individual's risk at an early age. However, the search for candidate genes has proven to be more complex, and their identification more elusive, than previously thought. This is largely due to the fact that much of the variability in risk results from interactions between the genome and environmental exposures. Whilst the former is now very well defined via the Human Genome Project, the latter (e.g. diet, toxins, physical activity) are poorly characterised, resulting in inability to account for their confounding effects in most large-scale candidate gene studies. The polygenic nature of most chronic diseases offers further complexity, requiring very large studies to disentangle relatively weak impacts of large numbers of potential 'risk' genes. The efficacy of diet as a preventative strategy could also be considerably increased by better information concerning gene polymorphisms that determine variability in responsiveness to specific diet and nutrient changes. Much of the limited available data are based on retrospective genotyping using stored samples from previously conducted intervention trials. Prospective studies are now needed to provide data that can be used as the basis for provision of individualised dietary advice and development of food products that optimise disease prevention. Application of the new technologies in nutrition research offers considerable potential for development of new knowledge and could greatly advance the role of diet as a preventative disease strategy in the 21st century. Given the potential economic and social benefits offered, funding for research in this area needs greater recognition, and a stronger strategic focus, than is presently the case. Application of genomics in human health offers considerable ethical and societal as well as scientific challenges. Economic determinants of health care provision are more likely to resolve such issues than scientific developments or altruistic concerns for human health.

The gut microbiota in obesity and metabolic disease - a novel therapeutic target

Obesity is sweeping the westernized world at a rate which far outstrips human genomic evolution, highlighting the importance of the obesogenic environment. Diet is an important component of this obesogenic environment, with certain diets (high fat, high refined carbohydrates and sugar) predisposing to overweight. On the other hand, there are also foods shown to protect against obesity and the diseases of obesity, including whole plant foods, dairy products, dietary fibre and functional foods like probiotics, prebiotics and phytochemicals. Interestingly, many of these foods mediate their health-promoting activities through the gut microbiota. The human gut microbiota itself has recently been identified as a contributory factor in this obesogenic environment, with differences observed between lean and obese. Evidence from human studies indicates that important groups of fermentative bacteria differ in abundance between lean and obese. Recently it has been suggested that anomalous microbiota composition in infancy can predispose to overweight in later life, highlighting the important role of optimal microbiota successional development, and that – as observed in laboratory animals – the gut microbiota may contribute to the aetiology of obesity. In this review we will introduce the gut microbiota, describe its interactions with major dietary components and the host, and then go on to discuss evidence indicating that the gut microbiota may contribute to the obesogenic environment. Finally, we will explore possible strategies for modulating the composition and activity of the human gut microbiota which may impact on obesity or the metabolic diseases associated with obesity. (Nutritional Therapy & Metabolism 2009; 27: 113-33)

Diet, ageing and genetic factors in the pathogenesis of diverticular disease

Diverticular disease (DD) is an age-related disorder of the large bowel which may affect half of the population over the age of 65 in the UK. This high prevalence ranks it as one of the most common bowel disorders in western nations. The majority of patients remain asymptomatic but there are associated life-threatening co-morbidities, which, given the large numbers of people with DD, translates into a considerable number of deaths per annum. Despite this public health burden, relatively little seems to be known about either the mechanisms of development or causality. In the 1970s, a model of DD formulated the concept that diverticula occur as a consequence of pressureinduced damage to the colon wall amongst those with a low intake of dietary fiber. In this review, we have examined the evidence regarding the influence of ageing, diet, inflammation and genetics on DD development. We argue that the evidence supporting the barotrauma hypothesis is largely anecdotal. We have also identified several gaps in the knowledge base which need to be filled before we can complete

Milk in the diet: good or bad for vascular disease?

CVD still represent the greatest cause of death and disease burden in Europe and there remains uncertainty whether or not diets rich in milk and/or dairy products affect CVD risk. This paper reviews current evidence on this from prospective studies and the role of serum lipids and blood pressure as markers of CVD risk with such diets. Also the potential of animal nutrition-based approaches aimed at reducing CVD risk from consumption of milk and dairy products is outlined. Briefly, the evidence from prospective studies indicates that increased consumption of milk does not result in increased CVD risk and may give some long-term benefits, although few studies relate specifically to cheese and butter and more information on the relationship between milk/dairy product consumption and dementia is needed. Recent data suggest that the SFA in dairy products may be less of a risk factor than previously thought; although this is based on serum cholesterol responses which taken in isolation may be misleading. Milk and some dairy products have counterbalancing effects by reducing blood pressure and possibly BMI control. Despite this, animal nutrition strategies to replace some SFA in milk with cis-MUFA or cis-PUFA are extensive and intuitively beneficial, although this remains largely unproven, especially for milk. There is an urgent need for robust intervention studies to evaluate such milk-fat modifications using holistic markers of CVD risk including central arterial stiffness.

Life and death in a civitas capital: metabolic disease and trauma in the children from late Roman Dorchester, Dorset

The impact that “Romanization” and the development of urban centers had on the health of the Romano-British population is little understood. A re-examination of the skeletal remains of 364 nonadults from the civitas capital at Roman Dorchester (Durnovaria) in Dorset was carried out to measure the health of the children living in this small urban area. The cemetery population was divided into two groups; the first buried their dead organized within an east–west alignment with possible Christian-style graves, and the second with more varied “pagan” graves, aligned north–south. A higher prevalence of malnutrition and trauma was evident in the children from Dorchester than in any other published Romano-British group, with levels similar to those seen in postmedieval industrial communities. Cribra orbitalia was present in 38.5% of the children, with rickets and/or scurvy at 11.2%. Twelve children displayed fractures of the ribs, with 50% of cases associated with rickets and/or scurvy, suggesting that rib fractures should be considered during the diagnosis of these conditions. The high prevalence of anemia, rickets, and scurvy in the Poundbury children, and especially the infants, indicates that this community may have adopted child-rearing practices that involved fasting the newborn, a poor quality weaning diet, and swaddling, leading to general malnutrition and inadequate exposure to sunlight. The Pagan group showed no evidence of scurvy or rib fractures, indicating difference in religious and child-rearing practices but that both burial groups were equally susceptible to rickets and anemia suggests a shared poor standard of living in this urban environment.

The role of animal nutrition in improving the nutritive value of animal-derived foods in relation to chronic disease

Foods derived from animals are an important source of nutrients in the diet; for example, milk and meat together provide about 60 and 55% of the dietary intake of Ca and protein respectively in the UK. However, certain aspects of some animal-derived foods, particularly their fat and saturated fatty acid (SFA) contents, have led to concerns that these foods substantially contribute to the risk of CVD, the metabolic syndrome and other chronic diseases. In most parts of Europe dairy products are the greatest single dietary source of SFA. The fatty acid composition of various animal-derived foods is, however, not constant and can, in many cases, be enhanced by animal nutrition. In particular, milk fat with reduced concentrations of the C12-16 SFA and an increased concentration of 18:1 MUFA is achievable, although enrichment with very-long-chain n-3 PUFA is much less efficient. However, there is now evidence that some animal-derived foods (notably milk products) contain compounds that may actively promote long-term health, and research is urgently required to fully characterise the benefits associated with the consumption of these compounds and to understand how the levels in natural foods can be enhanced. It is also vital that the beneficial effects are not inadvertently destroyed in the process of reducing the concentrations of SFA. In the future the role of animal nutrition in creating foods closer to the optimum composition for long-term human health is likely to become increasingly important, but production of such foods on a scale that will substantially affect national diets will require political and financial incentives and great changes in the animal production industry.

The role of meat as a source of n-3 polyunsaturated fatty acids in the human diet

It is considered that consumption of very long chain (VLC, carbon chain length >= 20) n - 3 PUFAs in most Western populations is sub-optimal and benefits in relation to chronic disease would be gained from increased consumption. This review examines the current contribution that meat makes to dietary intake of VLC n - 3 PUFA and given its current low contribution, how ruminant meat may be enriched. Enrichment both directly with VLC n - 3 fatty acids and indirectly by increasing intake by the animals of alpha-linolenic acid (ALNA; C 18:3 n - 3) are considered. Since it now appears that dietary ALNA is a very limited source of VLC n - 3 PUFA in humans, the indirect route is controversial but since some forages-are rich sources of ALNA this route has many sustainability and environmental attractions. Consideration is also given to the increased concentrations of trans and conjugated fatty acids that will arise from enriching ruminant meat with PUFA.

The role of meat as a source of n-3 polyunsaturated fatty acids in the human diet

It is considered that consumption of very long chain (VLC, carbon chain length >= 20) n - 3 PUFAs in most Western populations is sub-optimal and benefits in relation to chronic disease would be gained from increased consumption. This review examines the current contribution that meat makes to dietary intake of VLC n - 3 PUFA and given its current low contribution, how ruminant meat may be enriched. Enrichment both directly with VLC n - 3 fatty acids and indirectly by increasing intake by the animals of alpha-linolenic acid (ALNA; C 18:3 n - 3) are considered. Since it now appears that dietary ALNA is a very limited source of VLC n - 3 PUFA in humans, the indirect route is controversial but since some forages-are rich sources of ALNA this route has many sustainability and environmental attractions. Consideration is also given to the increased concentrations of trans and conjugated fatty acids that will arise from enriching ruminant meat with PUFA.

The neurokinin 1 receptor: a potential new target for anti-platelet therapy?

The important role of platelets in the development of arterial thrombosis and cardiovascular disease is well established. Current treatments for arterial thrombosis include anti-platelet agents such as aspirin, thienopyridines and glycoprotein IIb-IIIa inhibitors. Despite these drugs being effective there remains a substantial unmet clinical demand for more effective therapeutic approaches, which may reflect the existence of alternative underlying regulatory mechanisms to those already targeted. Recent publications have demonstrated a key role for tachykinins in the positive feedback regulation of platelet aggregation and thrombus formation. The pro-thrombotic effects of tachykinins on platelets are mediated through the neurokinin 1 receptor, which may therefore offer a novel therapeutic drug target in the prevention and the treatment of arterial thrombosis.