Receptor Heteromerization Expands the Repertoire of Cannabinoid Signaling in Rodent Neurons

A fundamental question in G protein coupled receptor biology is how a single ligand acting at a specific receptor is able to induce a range of signaling that results in a variety of physiological responses. We focused on Type 1 cannabinoid receptor (CB1R) as a model GPCR involved in a variety of processes spanning from analgesia and euphoria to neuronal development, survival and differentiation. We examined receptor dimerization as a possible mechanism underlying expanded signaling responses by a single ligand and focused on interactions between CB1R and delta opioid receptor (DOR). Using co-immunoprecipitation assays as well as analysis of changes in receptor subcellular localization upon co-expression, we show that CB1R and DOR form receptor heteromers. We find that heteromerization affects receptor signaling since the potency of the CB1R ligand to stimulate G-protein activity is increased in the absence of DOR, suggesting that the decrease in CB1R activity in the presence of DOR could, at least in part, be due to heteromerization. We also find that the decrease in activity is associated with enhanced PLC-dependent recruitment of arrestin3 to the CB1R-DOR complex, suggesting that interaction with DOR enhances arrestin-mediated CB1R desensitization. Additionally, presence of DOR facilitates signaling via a new CB1R-mediated anti-apoptotic pathway leading to enhanced neuronal survival. Taken together, these results support a role for CB1R-DOR heteromerization in diversification of endocannabinoid signaling and highlight the importance of heteromer-directed signal trafficking in enhancing the repertoire of GPCR signaling

Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction

Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality and, whilst smoking remains the single most important risk factor, COPD risk is heritable. Of 26 independent genomic regions showing association with lung function in genome-wide association studies, eleven have been reported to show association with airflow obstruction. Although the main risk factor for COPD is smoking, some individuals are observed to have a high forced expired volume in 1 second (FEV1) despite many years of heavy smoking. We # hypothesised that these ‘‘resistant smokers’’ may harbour variants which protect against lung function decline caused by smoking and provide insight into the genetic determinants of lung health. We undertook whole exome re sequencing of 100 heavy smokers who had healthy lung function given their age, sex, height and smoking history and applied three complementary approaches to explore the genetic architecture of smoking resistance. Firstly, we identified novel functional variants in the ‘‘resistant smokers’’ and looked for enrichment of these novel variants within biological pathways. Secondly, we undertook association testing of all exonic variants individually with two independent control sets. Thirdly, we undertook gene-based association testing of all exonic variants. Our strongest signal of association with smoking resistance for a non-synonymous SNP was for rs10859974 (P = 2.3461024) in CCDC38, a gene which has previously been reported to show association with FEV1/FVC, and we demonstrate moderate expression of CCDC38 in bronchial epithelial cells. We identified an enrichment of novel putatively functional variants in genes related to cilia structure and function in resistant smokers. Ciliary function abnormalities are known to be associated with both smoking and reduced mucociliary clearance in patients with COPD. We suggest that genetic influences on the development or function of cilia in the bronchial epithelium may affect growth of cilia or the extent of damage caused by tobacco smoke

Epidemiologia de internações por doença falciforme no Brasil Epidemiology of sickle cell disease hospital admissions in Brazil

OBJETIVO: A doença falciforme é uma enfermidade hereditária que afeta principalmente a população negra. O estudo teve por objetivo analisar as internações devido às complicações da doença, com enfoque nos aspectos epidemiológicos e clínicos. MÉTODOS: A população estudada foi constituída de 9.349 pacientes com diagnóstico de doença falciforme internados em hospitais da Bahia, Rio de Janeiro e São Paulo, no período de 2000 a 2002. Utilizaram-se os dados do Sistema de Internações Hospitalares do Sistema Único de Saúde. As variáveis respostas foram o óbito e o tempo médio de permanência hospitalar. As covariáveis foram o sexo, a idade, o tipo de admissão e a natureza jurídica do hospital. As proporções foram comparadas utilizando-se o teste qui-quadrado ou de Fischer; e para as variáveis contínuas, foi utilizado o teste Mann-Whitney ou Kruskall-Wallis. RESULTADOS: A mediana de idade variou de 11,0 a 12,0 anos e cerca de 70% das internações foram abaixo dos 20 anos. A mediana de dias de permanência hospitalar variou com a idade e o tipo de admissão. O tipo de admissão mais freqüente foi pela emergência (65,6 a 90,8%). Foi observada maior letalidade hospitalar entre adultos. A mediana da idade do óbito foi baixa (26,5 a 31,5 anos). CONCLUSÕES: Os resultados confirmaram a alta morbidade na população jovem e evidenciaram predominância de óbitos entre adultos jovens.<br>OBJECTIVE: Sickle cell disease is a hereditary disease, which affects mainly the black population. The aim of the present study was to analyze hospital admissions due to acute events resulting from sickle cell disease, at the epidemiological and clinical levels. METHODS: The study population included 9,349 patients with sickle cell disease admitted to hospitals in Bahia, Rio de Janeiro, and Sao Paulo, between 2000 and 2002. The national hospital database of the Brazilian Healthcare System was used. Response variables were death and mean duration of hospital admission. Covariables included sex, age, type of admission, and hospital legal status. Proportions were compared using Chi-square or Fischer tests; for continuous variables, the Mann-Whitney or Kruskall-Wallis tests were used. RESULTS: Median age ranged between 11.0 and 12.0 years, and 70% of admissions were of patients below age 20 years. Length of stay varied with age and type of admission. Emergency rooms were the most frequent form of admission (65.6 to 90.8%). Mortality was higher among adults. Median age of death was low (26.5 to 31.5 years). CONCLUSIONS: Our results confirm the high morbidity among youngsters and show a predominance of death among young adults

Genital morphology linked to social status in the bank vole (Myodes glareolus)

Lemaitre J-F, Ramm SA, Jennings N, Stockley P. Genital morphology linked to social status in the bank vole (Myodes glareolus). Behavioral Ecology and Sociobiology. 2012;66(1):97-105.Since genital morphology can influence the outcome of post-copulatory sexual selection, differences in the genitalia of dominant and subordinate males could be a factor contributing to the fertilisation advantage of dominant males under sperm competition. Here we investigate for the first time if penile morphology differs according to male social status in a promiscuous mammal, the bank vole (Myodes glareolus). In this species, dominant males typically achieve higher reproductive success than subordinates in post-copulatory sexual selection, and male genital morphology is complex, including both a baculum (os penis) and penile spines. Our results show that despite no difference in body size associated with male social status, baculum width is significantly larger in dominant male bank voles than in subordinates. We also found evidence of positive allometry and a relatively high coefficient of phenotypic variation in the baculum width of male bank voles, consistent with an influence of sexual selection. By contrast, baculum length and three measures of penile spinosity did not differ according to male social status or show evidence of positive allometry. We conclude that dominant male bank voles may benefit from an enlarged baculum under sperm competition and/or cryptic female choice and that differences in penile morphology according to male social status might be important but as yet largely unexplored source of variation in male reproductive success