Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Central nervous system (CNS) astrocytes release guanosine extracellularly, that exerts trophic effects. In CNS, extracellular guanosine (GUO) stimulates mitosis, synthesis of trophic factors, and cell differentiation, including neuritogenesis, is neuroprotective, and reduces apoptosis due to several stimuli. Specific receptor-like binding sites for eGUO in the nervous system may mediate its effects through both MAP kinase and PI3-kinase signalling pathways. Extracellular guanine (eGUA) also exerts several effects; the trophic effects of eGUO are likely regulated by conversion of eGUO to eGUA by a membrane located purine nucleoside phosphorylase (ecto-PNP) and by conversion of eGUA to xanthine by guanine deaminase.
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PMID:Neurotrophic effects of extracellular guanosine. 1860 May 24

Alterations in dendrite branching and morphology are present in many neurodegenerative diseases. These variations disrupt postsynaptic transmission and affect neuronal communication. Thus, it is important to understand the molecular mechanisms that regulate dendritogenesis and how they go awry during disease states. Previously, our laboratory showed that cypin, a mammalian guanine deaminase, increases dendrite number when overexpressed and decreases dendrite number when knocked down in cultured hippocampal neurons. Here, we report that exposure to brain-derived neurotrophic factor (BDNF), an important mediator of dendrite arborization, for 72 h but not for 24 h or less increases cypin mRNA and protein levels in rat hippocampal neurons. BDNF signals through cypin to regulate dendrite number, since knocking down cypin blocks the effects of BDNF. Furthermore, BDNF increases cypin levels via mitogen-activated protein kinase and transcription-dependent signaling pathways. Moreover, the cypin promoter region contains putative conserved cAMP response element (CRE) regions, which we found can be recognized and activated by CRE-binding protein (CREB). In addition, exposure of the neurons to BDNF increased CREB binding to the cypin promoter and, in line with these data, expression of a dominant negative form of CREB blocked BDNF-promoted increases in cypin protein levels and proximal dendrite branches. Together, these studies suggest that BDNF increases neuronal cypin expression by the activation of CREB, increasing cypin transcription leading to increased protein expression, thus identifying a novel pathway by which BDNF shapes the dendrite network.
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PMID:BDNF-promoted increases in proximal dendrites occur via CREB-dependent transcriptional regulation of cypin. 2171 38

Mounting evidence suggests that the guanine-based purines stand out as key player in cell metabolism and in several models of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases. Guanosine (GUO) and guanine (GUA) are extracellular signaling molecules derived from the breakdown of the correspondent nucleotide, GTP, and their intracellular and extracellular levels are regulated by the fine-tuned activity of two major enzymes, purine nucleoside phosphorylase (PNP) and guanine deaminase (GDA). Noteworthy, GUO and GUA, seem to play opposite roles in the modulation of cognitive functions, such as learning and memory. Indeed GUO, despite exerting neuroprotective, anti-apoptotic and neurotrophic effects, causes a decay of cognitive activities, whereas GUA administration in rats results in working memory improvement (prevented by L-NAME pre-treatment). This study was designed to investigate, in a model of SH-SY5Y neuroblastoma cell line, the signal transduction pathway activated by extracellular GUA. Altogether, our results showed that: (i) in addition to an enhanced phosphorylation of ASK1, p38 and JNK, likely linked to a non-massive and transient ROS production, the PKB/NO/sGC/cGMP/PKG/ERK cascade seems to be the main signaling pathway elicited by extracellular GUA; (ii) the activation of this pathway occurs in a pertussis-toxin sensitive manner, thus suggesting the involvement of a putative G protein coupled receptor; (iii) the GUA-induced NO production, strongly reduced by cell pre-treatment with L-NAME, is negatively modulated by the EPAC-cAMP-CaMKII pathway, which causes the over-expression of GDA that, in turn, reduces the levels of GUA. These molecular mechanisms activated by GUA may be useful to support our previous observation showing that GUA improves learning and memory functions through the stimulation of NO signaling pathway, and underscore the therapeutic potential of oral administration of guanine for treating memory-related disorders.
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PMID:Uncovering the Signaling Pathway behind Extracellular Guanine-Induced Activation of NO System: New Perspectives in Memory-Related Disorders. 2951 43