Evidence that the sigma(1) receptor is not directly coupled to G proteins.
ABSTRACT Sigma (sigma) receptors have been implicated in psychosis, cognition, neuroprotection, and locomotion in the central nervous system. The signal transduction mechanisms for sigma receptors have not been fully elucidated. In this study, we examined the possible coupling between sigma(1) receptors and heterotrimeric guanine nucleotide-binding proteins (G proteins) in rodent brain. In sigma(1) receptor-rich cerebellar membrane preparations, the competitive binding curves of two sigma(1) agonists, (+)pentazocine and 1S,2R-(-)-cis-N-[2-(3, 4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)cyclohexylamine (BD737), were unaffected by the addition of 10 microM guanosine-5'-O-(gamma-thio)-triphosphate (GTPgammaS). Neither (+)pentazocine (1-100 microM) nor BD737 (0.01-10 microM) stimulated GTPase activities significantly above basal levels in agonist-stimulated GTPase activity assays in cerebellar membranes. Furthermore, when using the method of agonist-stimulated [35S]GTPgammaS binding as assessed by autoradiography, we did not observe significant stimulation of [35S]GTPgammaS binding in rat brain sections by either (+)pentazocine or BD737. The above results demonstrate that the sigma(1) receptor is not likely be directly coupled to G proteins.
- SourceAvailable from: José Francisco NavarroPsiquiatria Biologica 01/2004; 11(2):41-57.
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ABSTRACT: ASIC1a channels play a major role in various pathophysiological conditions including depression, anxiety, epilepsy, and neurodegeneration following ischemic stroke. Sigma-1 (σ-1) receptor stimulation depresses the activity of ASIC1a channels in cortical neurons, but the mechanism(s) by which σ-1 receptors exert their influence on ASIC1a remains unknown. Experiments were undertaken to elucidate the signaling cascade linking σ-1 receptors to ASIC1a channels. Immunohistochemical studies showed that σ-1 receptors, ASIC1a and A-kinase anchoring peptide 150 colocalize in the plasma membrane of the cell body and processes of cortical neurons. Fluorometric Ca(2+) imaging experiments showed that disruption of the macromolecular complexes containing AKAP150 diminished the effects of the σ-1 on ASIC1a, as did application of the calcineurin inhibitors, cyclosporin A and FK-506. Moreover, whole-cell patch clamp experiments showed that σ-1 receptors were less effective at decreasing ASIC1a-mediated currents in the presence of the VIVIT peptide, which binds to calcineurin and prevents cellular effects dependent on AKAP150/calcineurin interaction. The coupling of σ-1 to ASIC1a was also disrupted by preincubation of the neurons in the G-protein inhibitor, pertussis toxin (PTX). Taken together, our data reveal that σ-1 receptor block of ASIC1a function is dependent on activation of a PTX-sensitive G-protein and stimulation of AKAP150 bound calcineurin.Neurochemical Research 06/2014; · 2.55 Impact Factor
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ABSTRACT: The advent of the selective serotonin reuptake inhibitors (SSRIs) is generally considered to have improved the treatment of depression. Head-to-head trials comparing SSRIs to each other have shown little difference in efficacy among agents. The main differences between the SSRIs relate to safety and tolerability profiles, reflecting the fact that the SSRIs possess significant and variable secondary pharmacological properties. This heterogeneity contributes to clinically relevant differences that clinicians are increasingly using to select antidepressant treatment more closely appropriate to specific patient populations and circumstances. This review assesses the place of fluvoxamine amongst the SSRIs in the context of current issues and concerns with drug therapy. Fluvoxamine has a proven efficacy and safety profile in treating elderly patients with depression. The beneficial effects of fluvoxamine in obsessive-compulsive disorder (OCD) are also well documented. On the other hand, its σ1-receptor binding profile may account for the observed high level of efficacy in psychotic depression and may explain the benefit of fluvoxamine in treating depression comorbid with anxiety/stress. There is no definitive evidence that suicide risk is higher with SSRIs than with other antidepressants or nonpharmacological treatments and postmarketing surveillance indicates that fluvoxamine is not associated with a higher level of suicidality.International Journal of Psychiatry in Clinical Practice 07/2009; 11(3):233-238. · 1.31 Impact Factor