Of the vertebrate senses, touch is the least understood at the molecular level The ion channels that form the core of the mechanosensory complex and confer touch sensitivity remain unknown. However, the similarity of the brain sodium channel 1 (BNC1) to nematode proteins involved in mechanotransduction indicated that it might be a part of such a mechanosensor. Here we show that disrupting the mouse BNC1 gene markedly reduces the sensitivity of a specific component of mechanosensation: low-threshold rapidly adapting mechanoreceptors. In rodent hairy skin these mechanoreceptors are excited by hair movement. Consistent with this function, we found BNC1 in the lanceolate nerve endings that lie adjacent to and surround the hair follicle. Although BNC1 has been proposed to have a role in pH sensing, the acid-evoked current in cultured sensory neurons and the response of acid-stimulated nociceptors were normal in BNC1 null mice. These data identify the BNC1 channel as essential for the normal detection of light touch and indicate that BNC1 may be a central component of a mechanosensory complex.

Cation channels in the DEG/ENaC family are proposed to detect cutaneous stimuli in mammals. We localized one such channel, DRASIC, in several different specialized sensory nerve endings of skin, suggesting it might participate in mechanosensation and/or acid-evoked nociception. Disrupting the mouse DRASIC gene altered sensory transduction in specific and distinct ways. Loss of DRASIC increased the sensitivity of mechanoreceptors detecting light touch, but it reduced the sensitivity of a mechanoreceptor responding to noxious pinch and decreased the response of acid- and noxious heat-sensitive nociceptors. The data suggest that DRASIC subunits participate in heteromultimeric channel complexes in sensory neurons. Moreover, in different cellular contexts, DRASIC may respond to mechanical stimuli or to low pH to mediate normal touch and pain sensation.

Acidosis is associated with inflammation and ischemia and activates cation channels in sensory neurons. Inflammation also induces expression of FMRFamidelike neuropeptides, which modulate pain. We found that neuropeptide FF (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe amide) and FMRFamide (Phe-Met-Arg-Phe amide) generated no current on their own but potentiated H+-gated currents from cultured sensory neurons and heterologously expressed ASIC and DRASIC channels. The neuropeptides slowed inactivation and induced sustained currents during acidification. The effects were specific; different channels showed distinct responses to the various peptides. These results suggest that acid-sensing ion channels may integrate multiple extracellular signals to modify sensory perception.

In the article by Price et al. (Neuron 32, 1071-1083 [December 20, 2001]), the x axis for stimulus response functions shown in Figures 3A-3F were incorrectly labeled and should read 50, 100, 200, and 400 m instead of 5, 10, 20, 40 m, as indicated in the original article. This error does not alter any of the conclusions made in the manuscript.

Background: Almost half of the world’s population uses coal and biomass fuels for domestic energy. Limited evidence suggests that exposure to air pollutants from indoor biomass combustion may be associated with elevated blood pressure (BP).Objective: Our aim was to assess the relationship between air pollution exposure from indoor biomass combustion and BP in women in rural China.Methods: We measured 24-hr personal integrated gravimetric exposure to fine particles < 2.5 µm in aerodynamic diameter (PM2.5) and systolic BP (SBP) and diastolic BP (DBP) in the winter and summer among 280 women ≥ 25 years of age living in rural households using biomass fuels in Yunnan, China. We investigated the association between PM2.5 exposure and SBP and DBP using mixed-effects models with random intercepts to account for correlation among repeated measures.Results: Personal average 24-hr exposure to PM2.5 ranged from 22 to 634 µg/m3 in winter and from 9 to 492 µg/m3 in summer. A 1-log-µg/m3 increase in PM2.5 exposure was associated with 2.2 mm Hg higher SBP [95% confidence interval (CI), 0.8 to 3.7; p = 0.003] and 0.5 mm Hg higher DBP (95% CI, –0.4 to 1.3; p = 0.31) among all women; estimated effects varied by age group. Among women > 50 years of age, a 1-log-µg/m3 increase in PM2.5 exposure was associated with 4.1 mm Hg higher SBP (95% CI, 1.5 to 6.6; p = 0.002) and 1.8 mm Hg higher DBP (95% CI, 0.4 to 3.2; p = 0.01). PM2.5 exposure was positively associated with SBP among younger women, but the association was not statistically significant.Conclusion: PM2.5 exposure from biomass combustion may be a risk factor for elevated BP and hence for cardiovascular events. Our findings should be corroborated in longitudinal studies.

Members of the DEG/ENaC protein family form ion channels with diverse functions. DEG/ENaC subunits associate as hetero-and homomultimers to generate channels; however the stoichiometry of these complexes is unknown. To determine the subunit stoichiometry of the human epithelial Na ؉ channel (hENaC), we expressed the three wild-type hENaC subunits (␣, ␤, and ␥) with subunits containing mutations that alter channel inhibition by methanethiosulfonates. The data indicate that hENaC contains three ␣, three ␤, and three ␥ subunits. Sucrose gradient sedimentation of ␣hENaC translated in vitro, as well as ␣-, ␤-, and ␥hENaC coexpressed in cells, was consistent with complexes containing nine subunits. FaNaCh and BNC1, two related DEG/ENaC channels, produced complexes of similar mass. Our results suggest a novel nine-subunit stoichiometry for the DEG/ENaC family of ion channels.The DEG/ENaC protein family includes channels with diverse physiologic and pathophysiologic functions. Epithelial Na ϩ channels (ENaC) absorb Na ϩ in kidney, lung, and intestine (1, 2), and mutations in human ENaC (hENaC) cause disease (3-6). Several family members from Caenorhabditis elegans, including MEC-4, MEC-10, and DEG-1, play a role in mechanotransduction, and some gain-of-function mutations cause neurodegeneration (7). In Helix aspersa, the FMRFamide-gated channel (FaNaCh) functions as a neurotransmitter receptor (8). Three family members have recently been identified in the mammalian nervous system, BNC1 (MDEG, BNaC1) (9 -11), BNaC2 (ASIC) (11,12), and DRASIC (13).All members of the DEG/ENaC family appear to function as multimers. ENaC contains three homologous subunits, ␣, ␤, and ␥ (14 -18). Functional studies show that simultaneous expression of all three subunits is required to generate maximal Na ϩ current, although expression of ␣ENaC alone can produce small currents. In addition, biochemical data show that the three human ENaC (hENaC) subunits associate (19). Genetic evidence suggests that MEC-4, MEC-10, and DEG-1 also function as heteromultimers (7,20). However, the subunit stoichiometry is not known for any DEG/ENaC channel.EXPERIMENTAL PROCEDURES cDNAs and mutations were generated as described previously (9,17,18). FaNaCh was amplified by polymerase chain reaction following reverse transcription of RNA from H. aspersa. We tagged the C terminus of ␣hENaC with the sequence DYKDDDDK (␣ Flag ) for immunoprecipitation by anti-Flag M2 monoclonal antibody. This did not alter the function of the ␣ subunit in Xenopus oocytes or epithelia or its ability to associate with other subunits (19).Wild-type or mutant ␣-, ␤-, and ␥hENaC (0.2 ng each) were expressed in Xenopus oocytes by nuclear injection of cDNA (18). When a mixture of wild-type and mutant cDNAs for a subunit was coinjected, the total amount of cDNA for the subunit remained constant. 16 -24 h after injection, whole-cell Na ϩ current was measured by two-electrode voltage clamp at Ϫ60 mV (bathing solution, 116 mM NaCl, 2 mM KCl, 0.4 mM CaCl 2 , 1 mM MgCl 2 , 5 mM HEPES, pH 7.4). To ...

OBJECTIVE -We investigated the association of the metabolic syndrome with new-onset diabetes in the Hong Kong Cardiovascular Risk Factor Prevalence Study cohort.RESEARCH DESIGN AND METHODS -We followed up on 1,679 subjects without diabetes at baseline. Those with a previous diagnosis of diabetes or those who were receiving drug treatment were considered to be diabetic. The remaining subjects underwent a 75-g oral glucose tolerance test (OGTT). Diabetes was defined by plasma glucose Ն7.0 mmol/l with fasting and/or Ն11.1 mmol/l at 2 h.RESULTS -The prevalences of the metabolic syndrome at baseline were 14.5 and 11.4%, respectively, according to U.S. National Cholesterol Education Program (NCEP) and International Diabetes Federation (IDF) criteria. After a median of 6.4 years, there were 66 and 54 new cases of diabetes in men and women, respectively. The metabolic syndrome at baseline predicted incident diabetes. Hazard ratios (HRs) for the NCEP and IDF definitions of the syndrome were 4.1 [95% CI 2.8 -6.0] and 3.5 [2.3-5.2], respectively. HRs for fasting plasma glucose (FPG) Ն6.1 or 5.6 mmol/l were 6.9 [4.1-11.5] and 4.1 [2.8 -6.0], respectively. The NCEP and IDF criteria had 41.9 and 31.7% sensitivity and 87.5 and 90.2% specificity, respectively. Their positive predictive values were low, ϳ20%, but their negative predictive values were ϳ95%.CONCLUSIONS -The metabolic syndrome, particularly its component, elevated FPG, predicts diabetes in Chinese. An individual without the metabolic syndrome is unlikely to develop diabetes, but one who has it should practice therapeutic lifestyle changes and have periodic FPG measurements to detect new-onset diabetes. Diabetes Care 30:1430-1436, 2007T he metabolic syndrome has been promoted as a clinical tool for identifying individuals predisposed to diabetes and/or adverse cardiovascular outcomes (1-7). Attempts have been made by different consensus groups to produce diagnostic criteria for the syndrome, but there is still some controversy. The pathogenetic mechanism underlying the metabolic syndrome remains uncertain, although central obesity and insulin resistance have been proposed to play a causative role. Because insulin resistance, together with hyperinsulinemia, is a fundamental metabolic abnormality in type 2 diabetes, the metabolic syndrome may be expected to be a good predictor of the development of the latter. Asians are thought to have a higher body fat percentage and cardiovascular risks than Caucasians at a given BMI (8). These factors raise concerns that definitions of the metabolic syndrome for Caucasians, when applied to Asian populations, would underestimate the population at risk of developing adverse outcomes such as type 2 diabetes, cardiovascular disease, and mortality. Therefore, validation of the predictive value of the metabolic syndrome needs to be established in population-based cohorts of different ethnicities. The International Diabetes Federation (IDF) proposed a new definition of the metabolic syndrome, which uses ethnicspecific central obesity cri...

Our results suggest that reducing overall PM pollution exposure in this population may be best achieved by reducing winter exposure. Behavioral interventions such as increasing ventilation during cooking or encouraging stove cleaning and maintenance may help achieve these reductions.