Receptor subtype and density determine the coupling repertoire of the 5-HT2 receptor subfamily

The 5-Hydroxytryptamine (5-HT)2C receptor (originally known as the 5-HT1C receptor) is a member of the 5-HT2 subfamily of G protein coupled receptors, which is known to couple to phospholipase C. Within the 5-HT2 subfamily, only the 5-HT2C receptor also coupled to inhibition of forskolin-stimulated cAMP production when expressed at high density (12 pmol/mg membrane protein) in stably transformed AV12 cells. The 5-HT2C receptor coupled with high efficacy to both phospholipase C as measured by IP3 (inositol 1,4,5-trisphosphate) production and to inhibition of forskolin-stimulated cAMP production (EC50 = 2.98 nM +/- 0.9 and IC50 = 47.99 nM +/- 10.25 respectively). The 5-HT2A and 5-HT2B receptors, while coupling to phospholipase C with high affinity (EC50s of 19.24 nM +/- 6.44 and 1.24 nM +/- 0.136 respectively), did not decrease adenylyl cyclase activity. The 5-HT2C receptor actions in both systems showed the expected pharmacology for the 5-HT2C receptor, e.g., mesulergine antagonized the effects of 5-HT and spiperone did not. Preincubation of cells with PTX showed that the G protein coupling of the 5-HT2C receptor to phospholipase C is PTX insensitive, while the G protein coupling to inhibition of adenylyl cyclase is PTX sensitive, even to concentrations as low as 20 ng/ml of PTX. PTX pretreatment of the 5-HT2C bearing cells also unmasked a small stimulatory effect on adenylyl cyclase. When expressed at low density the 5-HT2C receptor potentiated forskolin-stimulated cAMP production by 2 fold while still maintaining its ability to enhance PI hydrolysis. A more modest potentiation of cAMP production was noted with low density expression of the 5-HT2B receptor. Thus the ability of the 5-HT2C receptor to interact with several effectors through at least two different G proteins is, in part, receptor subtype specific but also influenced by receptor density.     

Distributed moment histogram: a neurophysiology based method of agonist and antagonist trunk muscle activity prediction

A neurocortical-based technique of muscle recruitment is presented to solve the muscle indeterminacy problem for lumbar torso modeling. Cortical recordings from behaving primates have established motor cortex cells that respond to a wide range of task directions, but are tuned to a preferred direction. A characteristic activity pattern of these neurons seems to be associated with effort direction. It was hypothesized that a model which recruits muscles based on a similar distribution would predict antagonistic muscle activity with greater realism than a widely referenced optimization formulation. The predictions of the Distributed Moment Histogram (DMH) method were evaluated under common speed (< 30 degrees s-1) sagittal plane lifting conditions using five subjects. The predicted forces showed high correspondence with agonist and antagonist myoelectric patterns. The mean coefficient of determination for the erector spinae was r2 = 0.91, and 0.41 for the latissimus. For the antagonistic muscles, the rectus abdominus was found to be electrically silent (< 3% MVC) and no activity was predicted by the method. The external oblique muscle was observed to be minimally active (< 16% MVC), and the DMH method predicted its mostly constant activity with a mean standard error of 1.6% MVC. The realistic antagonistic predictions supported the hypothesis and justify this cortical based technique as an alternative for muscle tension estimation in biomechanical torso modeling. A primary advantage of this method is its computational simplicity and direct physiologic analog.     

The relation of parent alcoholism to adolescent substance use: A longitudinal follow-up study.

The current study tested parent alcoholism effects on growth curves of adolescent substance use and examined whether parent and peer influences, temperamental emotionality and sociability, and stress and negative affect could explain parent alcoholism effects. Longitudinal latent growth curve modeling showed that adolescents with alcoholic fathers, boys, and adolescents with drug-using peers had steeper growth in substance use over time than did adolescents without alcoholic fathers, girls, and adolescents without drug-using peers. Data were consistent with father's monitoring and stress as possible mediators of paternal alcoholism effects. However, the direct effects of paternal alcoholism on substance use growth remained significant even after including the hypothesized mediators in the model. This suggests that other (unmeasured) mediators are necessary to fully explain paternal alcoholism risk for adolescents' escalating substance use over time. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effect of misleading questions in promoting nonconservation responses in children and adults.

In three studies we demonstrated that adults as well as children provide nonconservation-of-weight responses to misdirecting questions. The effect was constant over the types of problems studied, did not vary over the grade range tested (third graders through college students), and was resistant to a condition that had earlier proved successful in breaking a set to respond to misleading implications of questions. The results underscore the importance of linguistic pragmatics, conflicts with recent claims that among adults there is a certainty about and a belief in the necessity of certain types of Piagetian logic, and support earlier findings suggesting that contextual cues can alter responses to conservation questions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Real space transfer rates for polar optical phonon scattering from asymmetric quantum wells

We calculate the rate at which electrons bound in asymmetric semiconductor quantum wells are scattered out of the well by absorption or emission of polar optical phonons. The 2-D to 3-D nature of the scattering is included. The final states after scattering are states which carry current either to the right or left. We find that rates for scattering out of the well can be significantly smaller than bulk scattering rates. We also show that asymmetries in the well shape result in a directional dependence for the final state current. That is, electrons scatter out preferentially to the left or to the right depending on the details of the well potential.     

Positive modulation of human gamma-aminobutyric acid type A and glycine receptors by the inhalation anesthetic isoflurane

The interactions of the inhalation anesthetic agent isoflurane with ligand-gated chloride channels were studied using transient expression of recombinant human receptors in a mammalian cell line. Isoflurane enhanced gamma-aminobutyric acid (GABA)-activated chloride currents in cells that expressed heteromeric GABAA receptors consisting of combinations of alpha 1 or alpha 2, beta 1, and gamma 2 subunits and in cells that expressed receptors consisting of combinations of only alpha and beta subunits. Receptors consisting of alpha 2 and gamma 2 subunits were poorly expressed but were sensitive to isoflurane. Receptors consisting of beta 1 and gamma 2 subunits were not expressed. Isoflurane also enhanced glycine-activated chloride currents through homomeric alpha glycine receptors but did not enhance GABA currents in cells expressing homomeric rho 1 receptors. These results show that not all ligand-gated chloride channel receptors are sensitive to isoflurane and, therefore, that the anesthetic interacts with specific structural determinants of these ion channel proteins.     

Differential effects of methimazole and dexamethasone in avian muscular dystrophy

We showed previously that thyroid antagonists and glucocorticoids partially alleviated the impaired righting ability and abnormally high levels of plasma creatine kinase activity in genetically dystrophic chicks. The goals of the present study were: (1) to ascertain whether the beneficial effects of methimazole (MMI; thyroid antagonist) on muscle function and plasma creatine kinase (CK) activity in dystrophic chickens are correlated with significant reduction in plasma triiodothyronine (T3) and thyroxine (T4); (2) to assess whether the MMI-induced thyroid changes are accompanied by increased plasma corticosterone level and/or changes in muscle glucocorticoid receptors which might account partially for the beneficial effects of MMI; and (3) to determine if plasma T3 and T4 are reduced in dexamethasone (DEX) treated dystrophic chickens which might account at least partially for the beneficial effects of DEX (a potent glucocorticoid) on avian dystrophy. The data show that beneficial effects of MMI are associated with reduced plasma levels of thyroid hormones and increased circulating levels of corticosterone. In addition, DEX actually increases plasma T3 levels. These differential effects indicate that reduced plasma thyroid hormone levels do not represent a common mechanism of beneficial drug effects in avian muscular dystrophy. On the other hand, elevated plasma glucocorticoid levels accompany the beneficial effects of both severe hypothyroidism and DEX treatment. The data also show that MMI induces down-regulation of muscle cytosolic glucocorticoid receptors which are higher than normal in dystrophic muscles.     

Low salt intake down-regulates the guanylin signaling pathway in rat distal colon

BACKGROUND & AIMS: Guanylin, an endogenous gastrointestinal peptide, causes the translocation of NaCl from interstitial fluid to the intestinal lumen. The aim of this study was to examine whether changes in dietary salt intake lead to compensatory changes in expression of the guanylin signaling pathway. METHODS: Rats received low-, normal-, or high-sodium diets for 1 week. Colonic guanylin expression was evaluated by Western and Northern blotting, rates of guanylin secretion by measuring biologically active guanylin released into the medium from colon explants, and expression of the guanylin receptor (C-type guanylate cyclase) by Northern blotting and bioassay. RESULTS: By every criterion, the low-salt diet reduced expression of guanylin to 30%-40% of the level found in control animals. Guanylin receptor expression was also decreased, although less dramatically and with a lower statistical significance. For both guanylin and guanylin receptor, the high-salt diet had no significant effect on expression. CONCLUSIONS: The data support the hypothesis that the guanylin pathway is down-regulated as an adaptive response to salt restriction.     

Effects of prenatal androgenization, melengestrol acetate, and Synovex-H on feedlot performance, carcass, and sensory traits of once-calved heifers

Three studies were designed using a 2 x 2 factorial arrangement of treatments within each experiment to evaluate the effects of various management techniques on growth and carcass traits of once-calved heifers. In Exp. 1, 33 yearling (16 control [C] and 17 prenatally androgenized [PA]) and 39 once-calved (20 C and 19 PA) nonpregnant heifers were used to evaluate the effects of age and PA. Once-calved heifers were approximately 31 kg heavier (P < .03) on-test, initially consumed 11% more (P < .01) DM, and gained 11% faster (P < .08), but had similar (P = .44) gain to feed ratios (.138 vs. .131) as yearlings. Growth performance was not affected by PA. The yearling and once-calved heifers were then slaughtered at approximately 707 and 1,080 d of age, respectively. Despite maturity differences (P < .01), marbling scores (P = .26) and percentage of choice carcasses (P = .27) were similar. However, on the basis of newly accepted grading changes, percentage of once-calved heifer carcasses grading choice decreased from 57.3 to 34.4%. Organoleptic properties did not differ. Experiments 2 and 3 were then conducted to evaluate effects of commercially available products (melengestrol acetate [MGA] and Synovex-H) on feedlot characteristics of heifers following weaning of their first calf. In Exp. 2, 48 once-calved Simmental-based heifers were fed during the summer to a constant compositional fat thickness of .8 cm. Experiment 3 was conducted in the late fall and early winter, during which 52 moderately sized heifers were fed for 116 d postweaning and slaughtered. Performance of heifers in Exp. 2 was not affected by MGA. However, heifers fed MGA in Exp. 3 gained 9% faster (P < .05) than controls. In Exp. 2, Synovex-H tended to improve ADG (P < .09) and feed efficiency (P < .07), but did not affect performance in Exp. 3. Most carcass traits were not affected by either treatment. Nonpregnant, once-calved heifers seem to have a large capacity for efficient weight gain as compared with yearling heifers. However, hormonal compounds, such as testosterone propionate provided pre- or postnatally (Synovex-H), and MGA do not appear to provide the consistent, positive responses often seen with younger, more typical feedlot heifers.