Disease relevance of Cxcr4

• Neurons were stimulated with the HIV envelope protein gp120(IIIB) or the endogenous CXCR 4 agonist, SDF-1 alpha [1].
• DEX pretreatment decreased CXCR4 receptor density in the penumbra and attenuated astrocytosis [2].
• Dexamethasone downregulates chemokine receptor CXCR4 and exerts neuroprotection against hypoxia/ischemia-induced brain injury in neonatal rats [2].
• The compound exhibits potent inhibitory activity against a panel of R5-(virus using the CCR5 coreceptor), X4-(virus using the CXCR4 coreceptor), and R5/X4 HIV-1 laboratory and clinical isolates of the B subtype (median EC50 of 0.04 microM) in culture assays [3].
• Both T140, a CXCR4 antagonist, and pertussis toxin (PTX), an inactivator of G protein-coupled receptors, abrogated these events [4].

Psychiatry related information on Cxcr4

• CXCR4, a G protein-coupled receptor for the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) was reported to have possible implications in brain development and AIDS-related dementia [5].

High impact information on Cxcr4

• The chemokine SDF-1/CXCL12 modulates the firing pattern of vasopressin neurons and counteracts induced vasopressin release through CXCR4 [6].
• Expression of stromal cell-derived factor-1 and of its receptor CXCR4 in liver regeneration from oval cells in rat [7].
• At the early stages, from day 2 to day 4 in culture, CXCR4 is particularly concentrated at the leading edge of growing neurites [8].
• In conclusion, we demonstrate that SDF1alpha causes both proliferation and growth hormone release from pituitary adenoma cells, suggesting that the activation of CXCR4 may represent a novel regulatory mechanism for growth hormone secretion and pituitary cell proliferation, which may contribute to pituitary adenoma development [9].
• Thus, the stimulation of different p53 targets could be instrumental in determining the outcome of CXCR 4 activation on neuronal survival in neuro-inflammatory disorders [1].

Chemical compound and disease context of Cxcr4

• Immediate and neurotoxic effects of HIV protein gp120 act through CXCR4 receptor [10].

Biological context of Cxcr4

• Our data, therefore, suggest that in the Schwann cell lineage signal transduction cascades controlled by the activation of TNF- and CXCR4 receptors are functionally coupled [11].
• Finally, we could demonstrate that CXCR4 activation by SDF-1alpha increases the number of dying Schwann cells, indicating that this receptor/ligand interaction is modulating cell survival [11].
• Cyclic AMP and tumor necrosis factor-alpha regulate CXCR4 gene expression in Schwann cells [11].
• Identification of gp120 binding sites on CXCR4 by using CD4-independent human immunodeficiency virus type 2 Env proteins [12].
• Alanine-scanning mutagenesis of charged residues, tyrosines, and phenylalanines in extracellular CXCR4 domains implicated multiple amino acids in the N terminus (E14/E15, D20, Y21, and D22), ECL2 (D187, R188, F189, Y190, and D193), and ECL3 (D262, E268, E277, and E282) in binding, although minor differences were noted between VCP and ROD/B [12].

Anatomical context of Cxcr4

• We have investigated gene regulatory mechanisms acting on the expression of CXCR4 in cultured rat Schwann cells and found that receptor expression at transcript- and protein levels is directly dependent on intracellular cyclic AMP [11].
• Rat peripheral nerve Schwann cells have been shown to express the alpha-chemokine receptor CXCR4 as well as the corresponding ligand stromal cell-derived factor-1 (SDF-1) [11].
• Correspondingly, the SDF-1 receptor (termed CXCR4) can be demonstrated on stem cells of the external granular layer, but is absent on postmitotic cells commencing their final inward migration [13].
• By dual immunohistochemistry on brain sections, we clearly demonstrate that CXCR4 is constitutively expressed in adult rat brain, in glial cells (astrocytes, microglia but not oligodendrocytes) as well as in neurons [5].
• Neuronal expression of CXCR4 is mainly found in cerebral cortex, caudate putamen, globus pallidus, substantia innominata, supraoptic and paraventricular hypothalamic nuclei, ventromedial thalamic nucleus and substantia nigra [5].

Associations of Cxcr4 with chemical compounds

• Inhibition of CXCR 4 by AMD 3100 abrogates the effect of gp120 on both p53 and Apaf-1 [1].
• A localization of CXCR4 is thus observed in neuronal cell bodies expressing choline acetyltransferase-immunoreactivity in the caudate putamen and substantia innominata, as well as in tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta [5].
• Since the chemokine receptor CXCR4, specific for the SDF-1 alpha/CXCL12 ligand, regulates both apoptotic and neuroregeneration processes, this receptor was quantified 2 days following H/I in neonatal rat brain in relation with dexamethasone (DEX) treatment [2].
• Rat brain pericyte cell lines expressing beta2-adrenergic receptor, angiotensin II receptor type 1A, klotho, and CXCR4 mRNAs despite having endothelial cell markers [14].

Physical interactions of Cxcr4

• CONCLUSION: The rapid enhancement in CXCR4 chemokine receptor binding in the affected brain areas suggests that SDF-1 alpha/CXCR4 may play a role in the hypoxia-induced inflammatory reaction in the neonatal brain [2].

Other interactions of Cxcr4

• Thus, our data suggest that SDF1alpha may function through a CXCR4/ERK/Ets-linked signalling pathway in spinal cord neural development to modulate migration of progenitor cells [15].

Analytical, diagnostic and therapeutic context of Cxcr4

• In order to better understand the role of SDF-1 in the development of central neurons, we studied the cellular distribution of the SDF-1 receptor CXCR4 by immunocytochemistry of developing hippocampal neurons and tested the effect of SDF-1 in process patterning at the early stages of neuronal development [8].
• Using confocal microscopy, a differential distribution of CXCR4 in neuronal perikarya and dendrites can be observed according to the brain structure [5].
• The density of CXCR4 receptors was determined by quantitative autoradiography using [(125)I]SDF-1 alpha as a ligand [2].
• By using RT-PCR, immunoblot analysis, and immunofluorescence microscopy, we first showed expression of both CXCR4 and its ligand by IEC-6 cells [16].
• Sequence analysis and infectious recombinant viruses containing peripheral nerve-derived C2V3 sequences indicated a predominance of CCR5-dependent and macrophage-tropic HIV-1, although dual tropic viruses using both CCR5 and CXCR4 were identified [17].

References