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NADH regulates the release of calcium from the endoplasmic reticulum by modulation of inositol 1,4,5-trisphosphate receptors (I[P.sub.3]R), accounting for the augmented calcium release of hypoxic cells. We report selective binding of I[P.sub.3]R to GAPDH, whose activity leads to the local generation of NADH to regulate intracellular calcium signaling. This interaction requires cysteines 992 and 995 of I[P.sub.3]R and C150 of GAPDH. Addition of native GAPDH and NA[D.sup.+] to WT I[P.sub.3]R stimulates calcium release, whereas no stimulation occurs with C992S/995S I[P.sub.3]R that cannot bind GAPDH. Thus, the I[P.sub.3]R/ GAPDH interaction likely enables cellular energy dynamics to impact calcium signaling. calcium | hypoxia | metabolism

NADH regulates the release of calcium from the endoplasmic reticulum by modulation of inositol 1,4,5-trisphosphate receptors (IP3R), accounting for the augmented calcium release of hypoxic cells. We report selective binding of IP3R to GAPDH, whose activity leads to the local generation of NADH to regulate intracellular calcium signaling. This interaction requires cysteines 992 and 995 of IP3R and C150 of GAPDH. Addition of native GAPDH and NAD+ to WT IP3R stimulates calcium release, whereas no stimulation occurs with C992S/995S IP3R that cannot bind GAPDH. Thus, the IP3R/ GAPDH interaction likely enables cellular energy dynamics to impact calcium signaling. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Site-selective imaging can provide significant insight into the mechanism of HIV-associated neurological disease. The goal of this study was to evaluate the involvement of serotonergic transmission in HIV-associated depression using [11C]DASB, a serotonin transporter (5-HTT)-specific radiopharmaceutical for positron emission tomography (PET). Methods: Nine depressed HIV+ subjects (HIV-D), 9 non-depressed HIV+ subjects (HIV-ND) and 7 healthy controls (HC) underwent an MRI scan and a [11C]DASB-PET scan. The outcome measure was 5-HTT binding potential normalized to non-displaceable tissue radioligand (BPND). Results: HIV-ND subjects had lower mean regional 5-HTT BPND estimates across regions compared to HC, while HIV-D subjects demonstrated higher mean regional binding values than HIV-ND subjects in most regions. Prior to correction for the false discovery rate, HIV-ND had significantly lower BPND values compared to HC subjects in two regions (insula and anterior cingulate) and all HIV+ patients had significantly lower binding than HC in all regions except for the midbrain, thalamus and pons. After correction for the false discovery rate, only the insula showed significantly lower binding in HIV+ subjects compared to HC (P <0.0045). Despite a significant difference in the duration of illness between the HIV-D and HIV-ND groups, there was no definite correlation between the duration of illness and BPND. Conclusion: Lower [11C]DASB binding in HIV+ patients compared to HC may reflect serotonergic neuronal loss as a component of generalized HIV-associated neurodegeneration. Higher mean regional BPND values in HIV-D compared to HIV-ND subjects could reflect increased density of 5-HTT, leading to increased clearance of serotonin from the synapse, which could account, in part, for symptoms of depression. The lack of correlation between duration of illness and binding argues against these findings being the result of differential neurodegeneration only. Our findings suggest a possible role for dysregulated serotonergic transmission in HIV-associated depression. [Copyright &y& Elsevier]

Evidence suggests that depression in multiple sclerosis (MS) is largely biologically mediated by some of the same processes involved in the immunopathogenesis of this neurologic disease. In particular, the increase in proinflammatory cytokines, activation of the hypothalamic-pituitary-adrenal (HPA) axis, and reduction in neurotrophic factors that occur in MS may each account for the increased rate of depression seen in MS. The possible contributions of these neuroinflammatory, neuroendocrine, and neurotrophic mechanisms suggest a diverse array of novel treatment strategies for depression, both in the context of inflammatory conditions as well as in idiopathic depression. Furthermore, if such processes in MS play a causative role in the pathogenesis of depression, and depression in turn has affects on neurophysiological processes related to immune function, then treatment of depression might have a positive effect on MS disease progression. This makes treating MS depression a neuropsychiatric imperative.

Transverse Myelitis (TM) is a clinical syndrome in which an immune-mediated process causes neural injury to the spinal cord, resulting in varying degrees of weakness, sensory alterations and autonomic dysfunction. TM may exist as part of a multi-focal CNS disease (e.g. MS), multi-systemic disease (e.g. systemic lupus erythematosus), or as an isolated, idiopathic entity. In this article, we will summarize recent classification and diagnostic schemes (1), which provide a framework for the acute management of patients with TM. Additionally, we will review current concepts on the natural history, immunopathogenesis and treatment strategies for patients with TM.