1,721,190 research outputs found
Purinergic signalling: Pathophysiological roles
No full textIn this review, after a summary of the history and current status of the receptors involved in purinergic signalling, we focus on the distribution and physiological roles of purines and pyrimidines in both short-term events such as neurotransmission, exocrine and endocrine secretion and regulation of immune cell function, and long-term events such as cell growth, differentiation and proliferation in development and regeneration. Finally, the protective roles of nucleosides and nucleotides in events such as cancer, ischemia, wound healing, drug toxicity, inflammation and pain are explored and some suggestions made for future developments in this rapidly expanding field, with particular emphasis on the involvement of selective agonists and antagonists for purinergic receptor subtypes in therapeutic strategies
PURINOCEPTORS - ARE THERE FAMILIES OF P2X AND P2Y PURINOCEPTORS
No full textThere has been an exponential growth in interest n purinoceptors since the potent effects of purines were first reported in 1929 and purinoceptors defined in 1978. A distinction between P1 (adenosine) and P2 (ATP/ADP) purinoceptors was recognized at that time and later, A1 and A2, as well as P2X and P2Y subclasses of P1 and P2 purinoceptors were also defined. However, in recent years, many new subclasses have been claimed, particularly for the receptors to nucleotides, including P2t, P2z, P2u(n) and P2D, and there is some confusion now about how to incorporate additional discoveries concerning the responses of different tissues to purines. The studies beginning to appear defining the molecular structure of P2-purinoceptors subtypes are clearly going to be important in resolving this problem, as well as the introduction of new compounds that can discriminate pharmacologically between subtypes. Thus, in this review, on the basis of this new data and after a detailed analysis of the literature, we propose that: 1. (1) P2X(ligand-gated) and P2Y(G-protein-coupled) puriceptor families are established: 2. (2) four subclasses of P2X-purinoceptor can be identified (P2X1-P2X4) to date; 3. (3) the variously named P2-purinoceptors that are G-protein-coupled should be incorporated into numbered subclasses of the P2Y family. Thus: 1. P2Y1 represents the recently cloned P2Y receptor (clone 803) from chick brain; 2. P2Y2 represents the recently cloned P2u (or P2n) receptor from neuroblastoma, human epithelial and rat heart cells; 3. P2Y3 represents the recently cloned P2Y receptor (clone 103) from chick brain that resembles the former P2t receptor; 4. P2Y4-P2Y6 represent subclasses based on agonist potencies of newly synthesised analogues; 5. P2Y7 represents the former P2D receptor for dinucleotides. This new framework for P2 purinoceptors would be fully consistent with what is emerging for the receptors to other major transmitters, such as acetylcholine, γ-aminobutyric acid, glutamate and serotonin, where two main receptor families have been recognised, one mediating fast receptor responses directly linked to an ion channel, the other mediating slower responses through G-proteins. We fully expect discussion on the numbering of the different receptor subtypes within the P2X and P2Y families, but believe that this new way of defining receptors for nucleotides, based on agonist potency order, transduction mechanisms and molecular structure, will give a more ordered and logical approach to accomodating new findings. Moreover, based on the extensive literature analysis that led to this proposal, we suggest that the development of selective antagonists for the different P2-purinoceptor subtypes is now highly desirable, particularly for therapeutic purposes
Trophic actions of extracellular nucleotides and nucleosides on glial and neuronal cells
No full textIn addition to their well-established roles as neurotransmitters and neuromodulators, growing evidence suggests that nucleotides and nucleosides might also act as trophic factors in both the central and peripheral nervous systems. Specific extracellular receptor subtypes for these compounds are expressed on neurons, glial and endothelial cells, where they mediate strikingly different effects. These range from induction of cell differentiation and apoptosis, mitogenesis and morphogenetic changes, to stimulation of synthesis or release, or both, of cytokines and neurotrophic factors, both under physiological and pathological conditions. Nucleotides and nucleosides might be involved in the regulation of development and plasticity of the nervous system, and in the pathophysiology of neurodegenerative disorders. Receptors for nucleotides and nucleosides could represent a novel target for the development of therapeutic strategies to treat incurable diseases of the nervous system, including trauma- and ischemia-associated neurodegeneration, demyelinating and aging-associated cognitive disorders
MODULATION OF ASTROGLIAL CELL-PROLIFERATION BY ANALOGS OF ADENOSINE AND ATP IN PRIMARY CULTURES OF RAT STRIATUM
No full textWe have studied the possible purinoceptor-mediated modulation of astroglial cell proliferation in neuron-glia primary cultures obtained from rat corpus striatum. Cultures were grown for three days in the presence of either 2-chloro-adenosine or αβ-methylene-ATP (which behave as agonists of adenosine/ P1 and ATP/P2 purinoceptors, respectively), and then immunostained with an antibody to glial fibrillary acidic protein. 2-Chloro-adenosine decreased and αβ-methylene-ATP increased the number of astroglial cells in culture. For both derivatives, the effect was dose-dependent. The effect of αβ-methylene-ATP was antagonized by the trypanoside suramin, suggesting the involvement of a suramin-sensitive P2 purinoceptor, whereas the effect of 2-chloro-adenosine was not reversed by the P1 purinoceptor antagonist p-sulphonyl-phenyl-theophylline, implying the activation of a xanthine-insensitive adenosine purinoceptor subtype. In order to evaluate the extent of astrocyte proliferation in the presence of these two analogues, some cultures were incubated with bromodeoxyuridine for 24 h before fixing, and then double-immunostained for glial fibrillary acidic protein and bromodeoxyuridine. The percentage of bromodeoxyuridine positive astrocytes was significantly increased after exposure to both agents. It is therefore concluded that purines can modulate astroglial cells in opposite ways, inducing decreases or increases of cell number by activation of P1 and P2 purinoceptors, respectively. For the P2 purinoceptor-mediated effect, there was a quantitative correlation between the percentage of bromodeoxyuridine positive astrocytes and the cell number. For the P1 purinoceptor-mediated effect, no apparent correlation between these two parameters was found. This suggests the activation of independent effects, which involve other mechanisms besides the stimulation of DNA synthesis, and which eventually result in a reduction of cell number. The possible relevance of these findings to in vivo regulation of astrocyte cell function as well as in trauma- and ischaemia-associated hypergliosis is discussed
OPPOSITE EFFECTS OF ADENOSINE AND ATP ANALOGS ON ASTROGLIAL CELLS IN RAT-BRAIN PRIMARY CULTURES
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Purinoceptors on central nervous system glial cells: functional and pathological implications
No full textPresence of constitutive endothelial nitric oxide synthase immunoreactivity in urothelial cells of hamster proximal urethra
No full textElectrical field stimulation caused frequency-dependent relaxations in precontracted strips of hamster proximal urethra, which were attenuated by L-N(G)-nitroarginine methyl ester (10(-4) M) and completely blocked by tetrodotoxin (10(-6) M). Strips of hamster urethra devoid of urothelium showed reduced relaxant responses to electrical field stimulation which were abolished by L-N(G)-nitroarginine methyl ester (10(-4) M). Western blot analysis showed the presence of a constitutive endothelial nitric oxide synthase in the urothelial layer, suggesting that urothelium may release nitric oxide in response to electrical field stimulation and that this release is blocked by tetrodotoxin. It is suggested that the urothelium may contribute to relaxations of the smooth muscle of hamster urethra produced by nerve stimulation
Extrinsic Purinergic Regulation of Neural Stem/Progenitor Cells: Implications for CNS Development and Repair
No full textThere has been tremendous progress in understanding neural stem cell (NSC) biology, with genetic and cell biological methods identifying sequential gene expression and molecular interactions guiding NSC specification into distinct neuronal and glial populations during development. Data has emerged on the possible exploitation of NSC-based strategies to repair adult diseased brain. However, despite increased information on lineage specific transcription factors, cell-cycle regulators and epigenetic factors involved in the fate and plasticity of NSCs, understanding of extracellular cues driving the behavior of embryonic and adult NSCs is still very limited. Knowledge of factors regulating brain development is crucial in understanding the pathogenetic mechanisms of brain dysfunction. Since injury-activated repair mechanisms in adult brain often recapitulate ontogenetic events, the identification of these players will also reveal novel regenerative strategies. Here, we highlight the purinergic system as a key emerging player in the endogenous control of NSCs. Purinergic signalling molecules (ATP, UTP and adenosine) act with growth factors in regulating the synchronized proliferation, migration, differentiation and death of NSCs during brain and spinal cord development. At early stages of development, transient and time-specific release of ATP is critical for initiating eye formation; once anatomical CNS structures are defined, purinergic molecules participate in calcium-dependent neuron-glia communication controlling NSC behaviour. When development is complete, some purinergic mechanisms are silenced, but can be re-activated in adult brain after injury, suggesting a role in regeneration and self-repair. Targeting the purinergic system to develop new strategies for neurodevelopmental disorders and neurodegenerative diseases will be also discussed.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo)CNPq (Conselho Nacional de Desenvolvimento Cientifico), BrazilCNPq (Conselho Nacional de Desenvolvimento Cientifico), BrazilItalian Ministero dell'Universita e della Ricerca (MIURItalian Ministero dellUniversita e della Ricerca (MIURPRIN-/COFIN program Project) [2006059022, 2008XFMEA3]PRIN/COFIN program Project)Fondazione Italiana Sclerosi Multipla (FISM)Fondazione Italiana Sclerosi Multipla (FISM) [COD. 2010/R/2
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