Treatment of rats with reserpine, an inhibitor of the vesicular monoamine transporter (VMAT), depletes norepinephrine (NE) and regulates NE transporter (NET) expression. The present study examined the molecular mechanisms involved in regulation of the NET by reserpine using cultured cells. Exposure of rat PC12 cells to reserpine for a period as short as 5 min decreased [ 3 H]NE uptake capacity, an effect characterized by a robust decrease in the V max of the transport of [ 3 H]NE. As expected, reserpine did not displace the binding of [ 3 H]nisoxetine from the NET in membrane homogenates. The potency of reserpine for reducing [ 3 H]NE uptake was dramatically lower in SK-N-SH cells that have reduced storage capacity for catecholamines. Reserpine had no effect on [ 3 H]NE uptake in HEK-293 cells transfected with the rat NET (293-hNET), cells that lack catecholamine storage vesicles. NET regulation by reserpine was independent of trafficking of the NET from the cell surface. Pre-exposure of cells to inhibitors of several intracellular signaling cascades known to regulate the NET, including Ca 2+ /Ca 2+ -calmodulin dependent kinase and protein kinases A, C and G, did not affect the ability of reserpine to reduce [ 3 H]NE uptake. Treatment of PC12 cells with the catecholamine depleting agent, α-methyl-p-tyrosine, increased [ 3 H]NE uptake and eliminated the inhibitory effects of reserpine on [ 3 H]NE uptake. Reserpine non-competitively inhibits NET activity through a Ca 2+ -independent process that requires catecholamine storage vesicles, revealing a novel pharmacological method to modify NET function. Further characterization of the molecular nature of reserpine's action could lead to the development of alternative therapeutic strategies for treating disorders known to be benefitted by treatment with traditional competitive NET inhibitors. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The norepinephrine transporter (NET) is a Na + /Cl --dependent transporter responsible for limiting the synaptic action of norepinephrine (NE). The function of the NET is inhibited by several psychotherapeutic drugs that directly bind to the NET, such as desipramine, cocaine, and atomoxetine. Besides acute drug effects on the NET, NET function is up-and downregulated by exposures to several drugs, by activation of specific signaling pathways, and by physiological conditions (Mandela and Ordway, 2006b). Drugs that regulate the NET include compounds that bind directly to the NET such as desipramine, and also drugs and substances such as acetylcholine, that activate receptors and/or intra...
Background. Irisin, an exercise-induced myokine and adipocytokine, has been reported to decrease in type 2 diabetic patients. Recently, several research studies indicated that circulating levels were correlated with bone mineral density (BMD). To evaluate bone metabolism, bone turnover markers (BTMs) should be included. However, with respect to newly diagnosed T2DM patients, the relevance of their irisin levels to their BTMs and BMD remains unclear. The investigation of serum irisin levels in patients who have been newly diagnosed with type 2 diabetes and illumination of the relationship between serum irisin levels and those two indices of BMD and BTMs mentioned above are the intention of this cross-sectional study. Methods. 66 new-onset type 2 diabetic patients (T2DM group), together with 82 control subjects (NGT group), were recruited in this study. Serum irisin concentrations and BTMs (including osteocalcin (OC), procollagen type 1 N-terminal propeptide (P1NP), and β-C-terminal telopeptides of type I collagen (β-CTX)) were determined by the enzyme-linked immunosorbent assay (ELISA). Glucose, lipid profile, and insulin were considered as measuring indicators as well. Dual-energy X-ray absorptiometry (DXA) was utilized to evaluate the indicator of BMD. Serum irisin, BTMs, and BMD were compared between diabetic patients and healthy individuals. Pearson and Spearman correlation analyses were applied as well to assess correlations between irisin and BTMs and BMD. Multiple stepwise regression analysis was conducted to identify the independent factors of irisin. ROC curve analyses were carried out for serum irisin prediction for osteoporosis/osteopenia (OP). Results. The serum levels of irisin, procollagen type 1, intact N-terminal propeptide (P1NP), and osteocalcin (OC) were evidently lower in T2DM subjects than in NGT subjects (10.90 ± 1.88 vs .11.69 ± 2.06 ng/mL, P < 0.05; 36.42(25.68,51.70) vs. 44.52(35.73,58.05)ng/ml, P < 0.05; 16.15(12.40,21.66) vs. 18.70(15.56, 23.22)ng/ml, P < 0.05). Among patients with T2DM, the circulating irisin level of those with OP was lower than that of normal BMD (9.98 ± 2.09 vs. 11.39 ± 1.57 ng/ml, P < 0.01); irisin had a negative correlation with β-C-terminal telopeptides of type I collagen (β-CTX) (r = −0.496, P < 0.001) and came back unrelated to Lumbar BMD; Lumbar BMD was negatively relevant to OC (r = −0.274, P < 0.05) and β-CTX (r = −0.410, P < 0.01). Multiple linear regression analyses of stepwise models implied that TG, LDL-C, and β-CTX were independently associated with serum irisin concentrations ( P < 0.01 or P < 0.05). Conclusion. Serum irisin level was declined in patients with type 2 diabetes diagnosed in the near term and had a certain association with bone turnover markers. It is suggested to consider irisin as a potential biomarker of bone metabolic disorder in T2DM patients with the initial diagnosis.
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