BackgroundSmall Rho-GTPases are critical mediators of neuronal plasticity and are involved in the pathogenesis of several psychiatric and neurological disorders. Rac-GTPase forms a multiprotein complex with upstream and downstream regulators that are essential for the spatiotemporal transmission of Rac signaling. The sigma-1 receptor (Sig1R) is a ligand-regulated membrane protein chaperone, and multiprotein complex assembly is essential to sigma-receptor function.ResultsUsing immunoprecipitation techniques, we have shown that in mitochondrial membranes Sig1R could directly interact with Rac1. Besides Rac1, the Sig1R forms complexes with inositol 1,4,5-trisphosphate receptor and Bcl2, suggesting that mitochondrial associated membranes (MAM) are involved in this macromolecular complex formation. Assembly of this complex is ligand-specific and depends on the presence of sigma agonist/antagonist, as well as on the presence of GTP/GDP. Treatment of mitochondrial membranes with (+)-pentazocine leads to the (+)-pentazocine-sensitive phosphorylation of Bad and the pentazocine-sensitive NADPH-dependent production of ROS.ConclusionWe suggest that Sig1R through Rac1 signaling induces mild oxidative stress that possibly is involved in the regulation of neuroplasticity, as well as in the prevention of apoptosis and autophagy.

Background: Estimating contractility of the left ventricle with noninvasive techniques is an important yet elusive goal. Positive inotropic interventions are mirrored by smaller end-systolic volumes and higher end-systolic pressures. An increased heart rate progressively increases the force of ventricular contraction (Bowditch treppe or staircase phenomenon). Aim: To assess the feasibility of a noninvasive estimation of force-frequency relation (FFR) during pacing stress in the echo lab in patients with permanent pacemaker (PM). Methods: Transthoracic stress pacing echocardiography was performed in 26 patients with a permanent pacemaker (age 69F11 years; 21 men, 5 women). Seven patients had normal function at baseline and during stress (bnormalsQ); eight had angiographically assessed coronary artery disease (three with and five without induced ischemia with stress echo); eleven patients had dilated cardiomyopathy (DC). To build the FFR, the force was determined at different steps as the ratio of the systolic pressure (SP, cuff sphygmomanometer)/end-systolic volume index (ESV, biplane Simpson rule/body surface area). Heart rate was determined from ECG. Results: The absolute value of the FFR slope was highest in controls and lowest in DC patients. A flat-downsloping FFR was found in 12/19 patients but not for normals ( pb0.01). Conclusions: Noninvasive pacemaker stress echocardiography (PASE) is a simple and efficient option to assess left ventricular (LV) contractility in patients with permanent pacemaker.

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Human T lymphocytes express both ionotropic and metabotropic glutamate receptors that control immune responses, cell activation, maturation and death. In this study, we examined the effect of N-methyl-D-aspartate (NMDA) and σ1-receptor ligands on the secretion of the proinflammatory chemokine interleukin 8 (IL-8) and the anti-inflammatory cytokine interleukin 10 (IL-10) in human leukemia Jurkat cells and peripheral blood lymphocytes (PBLs). We have shown that NMDA increased IL-8 and decreased IL-10 secretion and that σ-ligands modulated the action of NMDA. Moreover, the effects of NMDA and σ-ligands were interrelated with the nitric oxide (NO) content, suggesting that the intracellular concentration of NO could play a major role in the synthesis of cytokines. Western blots against the NR2A and NR2B subunits of the NMDA glutamate receptor revealed that long-term (48 h) treatment of PBLs with glutamate at concentrations within normal plasma levels (1 × 10^–5M), in contrast to low concentrations (0.3 × 10^–6M), downregulates the NR2A subunit, probably by internalization. Furthermore, we found that PBLs with noninternalized NR2A secreted less IL-10 than lymphocytes with downregulated NR2A; under these conditions, the transcriptional activity of NF-κB was increased whereas the transcriptional activity of c-Fos was decreased. These findings implicate that the activities of NF-κB and c-Fos control the expression of the IL8 and IL10 genes, depending on the subunit composition of the NMDA receptor. In conclusion, we suggest that lymphocytes express an active NMDA receptor only in a low-glutamate milieu.

The effects of 3,5,3'-triiodo-l-thyronine (T3) and l-thyroxine (T4) on the integrin αvβ3 receptor of thyroid hormones (TH) were investigated in pheochromocytoma PC-12 cells. Differentiation was induced by treatment of PC-12 cells with fisetin and the levels of phosphorylated extracellular signal-regulated kinase (ERK) and Akt in cytoplasm, as well as the content of FoxO6 transcription factor in nuclei was analysed in undifferentiated and differentiated conditions. We have found that in undifferentiated PC-12 cells, tetraiodothyroacetic acid (TETRAC), a known inhibitor of binding of T4 and T3 to plasma membrane integrin αvβ3 receptor inhibits T4-dependent phosphorylation of ERK, whereas in differentiated PC-12 cells, TETRAC abolishes the effect of T3. In undifferentiated PC-12 cells, both TH increase the level of p-Akt, and this enhancement is not sensitive to TETRAC. In differentiated PC-12 cells, both TH increase the level of p-Akt; however, only T3-dependent activation of Akt is sensitive to the TETRAC. Furthermore, our results have shown that in differentiated PC-12 cells, the expression of FoxO6 was higher than in undifferentiated PC-12 cells, and this elevation has not changed under the action of TH. Only in undifferentiated PC-12 cells the T3-dependent expression of FoxO6 was sensitive to the TETRAC. We propose that PC-12 cells contain integrin αvβ3 receptor, which T3 and T3/T4 sites are differentially regulated by TH in undifferentiated and differentiated conditions.