New insights into purinergic receptor signaling in neuronal differentiation, neuroprotection, and brain disorders.
Ontology highlight
ABSTRACT:
SUBMITTER: Majumder P
PROVIDER: S-EPMC2072925 | biostudies-other | 2007 Sep
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Primary cilia are conserved sensory hubs essential for signaling transduction and embryonic development. Ciliary dysfunction causes a variety of developmental syndromes with neurological features and cognitive impairment, whose basis mostly remains unknown. Despite connections to neural function, the primary cilium remains an overlooked organelle in the brain. Most neurons have a primary cilium; however, it is still unclear how this organelle modulates brain architecture and function, given the lack of any systemic dissection of neuronal ciliary signaling. Here, we present the first in vivo glance at the molecular composition of cilia in the mouse brain. We have adapted in vivo BioID (iBioID), targeting the biotin ligase BioID2 to primary cilia in neurons. We identified tissue-specific signaling networks enriched in neuronal cilia, including Eph/Ephrin and GABA receptor signaling pathways. Our iBioID ciliary network presents a wealth of neural ciliary hits that provides new insights into neurological disorders. Our findings are a promising first step in defining the fundamentals of ciliary signaling and their roles in shaping neural circuits and behavior. This work can be extended to pathological conditions of the brain, aiming to identify the molecular pathways disrupted in the brain cilium. Hence, finding novel therapeutic strategies will help uncover and leverage the therapeutic potential of the neuronal cilium.
| S-EPMC10769350 | biostudies-literature
Project description:Purinergic signaling regulates numerous vital biological processes in the central nervous system (CNS). The two principle purines, ATP and adenosine act as excitatory and inhibitory neurotransmitters, respectively. Compared to other classical neurotransmitters, the role of purinergic signaling in psychiatric disorders is not well understood or appreciated. Because ATP exerts its main effect on energy homeostasis, neuronal function of ATP has been underestimated. Similarly, adenosine is primarily appreciated as a precursor of nucleotide synthesis during active cell growth and division. However, recent findings suggest that purinergic signaling may explain how neuronal activity is associated neuronal energy charge and energy homeostasis, especially in mental disorders. In this review, we provide an overview of the synaptic function of mitochondria and purines in neuromodulation, synaptic plasticity, and neuron-glia interactions. We summarize how mitochondrial and purinergic dysfunction contribute to mental illnesses such as schizophrenia, bipolar disorder, autism spectrum disorder (ASD), depression, and addiction. Finally, we discuss future implications regarding the pharmacological targeting of mitochondrial and purinergic function for the treatment of psychiatric disorders.
| S-EPMC5036858 | biostudies-literature
Project description:Histone deacetylases (HADC) are the enzymes that remove acetyl group from lysine residue of histones and non-histone proteins and regulate the process of transcription by binding to transcription factors and regulating fundamental cellular process such as cellular proliferation, differentiation and development. In neurodegenerative diseases, the histone acetylation homeostasis is greatly impaired, shifting towards a state of hypoacetylation. The histone hyperacetylation produced by direct inhibition of HDACs leads to neuroprotective actions. This review attempts to elaborate on role of small molecule inhibitors of HDACs on neuronal differentiation and throws light on the potential of HDAC inhibitors as therapeutic agents for treatment of neurodegenerative diseases. The role of HDACs in neuronal cellular and disease models and their modulation with HDAC inhibitors are also discussed. Significance of these HDAC inhibitors has been reviewed on the process of neuronal differentiation, neurite outgrowth and neuroprotection regarding their potential therapeutic application for treatment of neurodegenerative diseases.
| S-EPMC7194116 | biostudies-literature
Project description:Astrocyte-derived gliotransmitters glutamate and ATP modulate neuronal activity. It remains unclear, however, how astrocytes control the release and coordinate the actions of these gliotransmitters. Using transgenic expression of the light-sensitive channelrhodopsin 2 (ChR2) in astrocytes, we observed that photostimulation reliably increases action potential firing of hippocampal pyramidal neurons. This excitation relies primarily on a calcium-dependent glutamate release by astrocytes that activates neuronal extra-synaptic NMDA receptors. Remarkably, our results show that ChR2-induced Ca2+ increase and subsequent glutamate release are amplified by ATP/ADP-mediated autocrine activation of P2Y1 receptors on astrocytes. Thus, neuronal excitation is promoted by a synergistic action of glutamatergic and autocrine purinergic signaling in astrocytes. This new mechanism may be particularly relevant for pathological conditions in which ATP extracellular concentration is increased and acts as a major danger signal.
| S-EPMC5595839 | biostudies-other
Project description:BACKGROUND:Lymphotoxin (LT) is a lymphokine mainly expressed in lymphocytes. LT? binds one or two membrane-associated LT? to form LT?2?1 or LT?1?2 heterotrimers. The predominant LT?1?2 binds to LT? receptor (LT?R) primarily expressed in epithelial and stromal cells. Most studies on LT?R signaling have focused on the organization, development, and maintenance of lymphoid tissues. However, the roles of LT?R signaling in the nervous system, particularly in neurogenesis, remain unknown. Here, we investigated the role of LT?R-mediated NF?B signaling in regulating neural lineage differentiation. METHODS:The C57BL/6J wild-type and GFAP-dnI?B? transgenic mice were used. Serum-free embryoid bodies were cultured from mouse embryonic stem cells and further induced into neural stem/progenitor cells (NSCs/NPCs). Primary neurospheres were cultured from embryonic and adult mouse brains followed by monolayer culture for amplification/passage. NF?B activation was determined by adenovirus-mediated NF?B-firefly-luciferase reporter assay and p65/RelB/p52 nuclear translocation assay. LT?R mRNA expression was evaluated by quantitative RT-PCR and LT?R protein expression was determined by immunohistochemistry and Western blot analysis. Multilabeled immunocytochemistry or immunohistochemistry followed by fluorescent confocal microscopy and quantitative analysis of neural lineage differentiation were performed. Graphing and statistical analysis were performed with GraphPad Prism software. RESULTS:In cultured NSCs/NPCs, LT?1?2 stimulation induced an activation of classical and non-classical NF?B signaling. The expression of LT?R-like immunoreactivity in GFAP+/Sox2+ NSCs was identified in well-established neurogenic zones of adult mouse brain. Quantitative RT-PCR and Western blot analysis validated the expression of LT?R in cultured NSCs/NPCs and brain neurogenic regions. LT?R expression was significantly increased during neural induction. LT?1?2 stimulation in cultured NSCs/NPCs promoted astroglial and oligodendrocytic lineage differentiation, but inhibited neuronal lineage differentiation. Astroglial NF?B inactivation in GFAP-dnI?B? transgenic mice rescued LT?R-mediated abnormal phenotypes of cultured NSCs/NPCs. CONCLUSION:This study provides the first evidence for the expression and function of LT?R signaling in NSCs/NPCs. Activation of LT?R signaling promotes glial lineage differentiation. Our results suggest that neurogenesis is regulated by the adaptive immunity and inflammatory responses.
| S-EPMC5819232 | biostudies-literature
Project description:With the umbrella term 'neurodevelopmental disorders' (NDDs) we refer to a plethora of congenital pathological conditions generally connected with cognitive, social behavior, and sensory/motor alterations. Among the possible causes, gestational and perinatal insults have been demonstrated to interfere with the physiological processes necessary for the proper development of fetal brain cytoarchitecture and functionality. In recent years, several genetic disorders caused by mutations in key enzymes involved in purine metabolism have been associated with autism-like behavioral outcomes. Further analysis revealed dysregulated purine and pyrimidine levels in the biofluids of subjects with other NDDs. Moreover, the pharmacological blockade of specific purinergic pathways reversed the cognitive and behavioral defects caused by maternal immune activation, a validated and now extensively used rodent model for NDDs. Furthermore, Fragile X and Rett syndrome transgenic animal models as well as models of premature birth, have been successfully utilized to investigate purinergic signaling as a potential pharmacological target for these diseases. In this review, we examine results on the role of the P2 receptor signaling in the etiopathogenesis of NDDs. On this basis, we discuss how this evidence could be exploited to develop more receptor-specific ligands for future therapeutic interventions and novel prognostic markers for the early detection of these conditions.
| S-EPMC10216121 | biostudies-literature
Project description:Microglia are highly sensitive to even small changes in the brain environment, such as invasion of non-hazardous toxicants or the presymptomatic state of diseases. However, the physiological or pathophysiological consequences of their responses remain unknown. Here, we report that cultured microglia sense low concentrations of the neurotoxicant methylmercury (MeHg(low)) and provide neuroprotection against MeHg, for which astrocytes are also required. When exposed to MeHg(low), microglia exocytosed ATP via p38 MAPK- and vesicular nucleotide transporter (VNUT)-dependent mechanisms. Astrocytes responded to the microglia-derived ATP via P2Y1 receptors and released interleukin-6 (IL-6), thereby protecting neurons against MeHg(low). These neuroprotective actions were also observed in organotypic hippocampal slices from wild-type mice, but not in slices prepared from VNUT knockout or P2Y1 receptor knockout mice. These findings suggest that microglia sense and respond to even non-hazardous toxicants such as MeHg(low) and change their phenotype into a neuroprotective one, for which astrocytic support is required.
| S-EPMC3948352 | biostudies-literature
Project description:This review outlined evidence that purinergic signaling is involved in the modulation of blood-brain barrier (BBB) permeability. The functional and structural integrity of the BBB is critical for maintaining the homeostasis of the brain microenvironment. BBB integrity is maintained primarily by endothelial cells and basement membrane but also be regulated by pericytes, neurons, astrocytes, microglia and oligodendrocytes. In this review, we summarized the purinergic receptors and nucleotidases expressed on BBB cells and focused on the regulation of BBB permeability by purinergic signaling. The permeability of BBB is regulated by a series of purinergic receptors classified as P2Y1, P2Y4, P2Y12, P2X4, P2X7, A1, A2A, A2B, and A3, which serve as targets for endogenous ATP, ADP, or adenosine. P2Y1 and P2Y4 antagonists could attenuate BBB damage. In contrast, P2Y12-mediated chemotaxis of microglial cell processes is necessary for rapid closure of the BBB after BBB breakdown. Antagonists of P2X4 and P2X7 inhibit the activation of these receptors, reduce the release of interleukin-1 beta (IL-1β), and promote the function of BBB closure. In addition, the CD39/CD73 nucleotidase axis participates in extracellular adenosine metabolism and promotes BBB permeability through A1 and A2A on BBB cells. Furthermore, A2B and A3 receptor agonists protect BBB integrity. Thus, the regulation of the BBB by purinergic signaling is complex and affects the opening and closing of the BBB through different pathways. Appropriate selective agonists/antagonists of purinergic receptors and corresponding enzyme inhibitors could modulate the permeability of the BBB, effectively delivering therapeutic drugs/cells to the central nervous system (CNS) or limiting the entry of inflammatory immune cells into the brain and re-establishing CNS homeostasis.
| S-EPMC9941648 | biostudies-literature
Project description:When Clostridium tetani was discovered and identified as a Gram-positive anaerobic bacterium of the genus Clostridium, the possibility of turning its toxin into a valuable biological carrier to ameliorate neurodegenerative processes was inconceivable. However, the non-toxic carboxy-terminal fragment of the tetanus toxin heavy chain (fragment C) can be retrogradely transported to the central nervous system; therefore, fragment C has been used as a valuable biological carrier of neurotrophic factors to ameliorate neurodegenerative processes. More recently, the neuroprotective properties of fragment C have also been described in vitro and in vivo, involving the activation of Akt kinase and extracellular signal-regulated kinase (ERK) signaling cascades through neurotrophin tyrosine kinase (Trk) receptors. Although the precise mechanism of the molecular internalization of fragment C in neuronal cells remains unknown, fragment C could be internalized and translocated into the neuronal cytosol through a clathrin-mediated pathway dependent on proteins, such as dynamin and AP-2. In this review, the origins, molecular properties and possible signaling pathways of fragment C are reviewed to understand the biochemical characteristics of its intracellular and synaptic transport.
| S-EPMC3397502 | biostudies-literature
Project description:Neurotrophins are essential for neuronal differentiation, but the onset and the intensity of neurotrophin signaling within the neuronal microenvironment are poorly understood. We tested the hypothesis that extracellular nucleotides and their cognate receptors regulate neurotrophin-mediated differentiation. We found that 5'-O-(3-thio)triphosphate (ATPgammaS) activation of the G protein-coupled receptor P2Y(2) in the presence of nerve growth factor leads to the colocalization and association of tyrosine receptor kinase A and P2Y(2) receptors and is required for enhanced neuronal differentiation. Consistent with these effects, ATPgammaS promotes phosphorylation of tyrosine receptor kinase A, early response kinase 1/2, and p38, thereby enhancing sensitivity to nerve growth factor and accelerating neurite formation in both PC12 cells and dorsal root ganglion neurons. Genetic or small interfering RNA depletion of P2Y(2) receptors abolished the ATPgammaS-mediated increase in neuronal differentiation. Moreover, in vivo injection of ATPgammaS into the sciatic nerve increased growth-associated protein-43 (GAP-43), a marker for axonal growth, in wild-type but not P2Y(2)(-/-) mice. The interactions of tyrosine kinase- and P2Y(2)-signaling pathways provide a paradigm for the regulation of neuronal differentiation and suggest a role for P2Y(2) as a morphogen receptor that potentiates neurotrophin signaling in neuronal development and regeneration.
| S-EPMC1323158 | biostudies-literature