1,721,042 research outputs found
P1 and P2 receptors in cell growth and differentiation
No full textBesides their well-established roles as short-term neurotransmitters, nucleotides and nucleosides are also potent regulators of cell growth and differentiation. Compelling evidence obtained on neural, immune, cardiovascular and respiratory system cells, as well as on many other cell types, suggests that these compounds may act as physiological regulators of the phenotype, proliferation and apoptosis of target cells, with a potential in both development and maturation, and in tissue repair and remodeling after trauma and ischemia. Studies by several authors have also made clear that the trophic actions of nucleotides and nucleosides may be either direct or mediated by modulation of synthesis and release of secondary trophic substances (e.g., polypeptidic growth factors and cytokines). In many instances, the involvement of specific P1 or P2 receptors has been established, which discloses the possibility of regulating the local production of neurotrophins, pleiotrophis, cytokines and other trophic agents via selective purinoceptor ligands. The pharmacological modulation of these receptors may therefore have a therapeutic potential in various diseases, ranging from cancer and neurodegenerative disorders, to prevention of recurrent stroke and promotion of wound and gastric ulcer healing
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
AGONIST-INDUCED CHANGES OF ADENOSINE-A1 AND ADENOSINE-A2 RECEPTOR FUNCTION IN RAT-BRAIN SLICES
No full textAdenosine Signaling in Glioma Cells
No full textPurines and pyrimidines are fundamental signaling molecules in controlling the survival and proliferation of astrocytes, as well as in mediating cell-to-cell communication between glial cells and neurons in the healthy brain. The malignant transformation of astrocytes towards progressively more aggressive brain tumours (from astrocytoma to anaplastic glioblastoma) leads to modifications in both the survival and cell death pathways which overall confer a growth advantage to malignant cells and resistance to many cytotoxic stimuli. It has been demonstrated, however, that, in astrocytomas, several purinergic (in particular adenosinergic) pathways controlling cell survival and death are still effective and, in some cases, even enhanced, providing invaluable targets for purine-based chemotherapy, that still represents an appropriate pharmacological approach to brain tumours. In this chapter, the current knowledge on both receptor-mediated and receptor-independent adenosine pathways in astrocytomas will be reviewed, with a particular emphasis on the most promising targets which could be translated from in vitro studies to in vivo pharmacology. Additionally, we have included new original data from our laboratory demonstrating a key involvement of MAP kinases in the cytostastic and cytotoxic effects exerted by an adenosine analogue, 2-CdA, which with the name of Cladribine is already clinically utilized in haematological malignancies. Here we show that 2-CdA can activate multiple intracellular pathways leading to cell cycle block and cell death by apoptosis of a human astrocytoma cell line that bears several pro-survival genetic mutations. Although in vivo data are still lacking, our results suggest that adenosine analogues could therefore be exploited to overcome resistance to chemotherapy of brain tumours
IN VIVO MODULATION OF STRIATAL PHOSPHOPROTEINS BY DOPAMINERGIC AGENTS
No full textProtein phosphorylation in the brain represents a common target for several second messenger systems. A phosphoprotein (DARPP-32) specifically regulated by cAMP and dopamine has been detected in neurons bearing dopamine D-1 receptors, where it plays a key role in eliciting cAMP-mediated intracellular responses. The endogenous phosphorylation of this cytosolic protein is markedly affected after in vivo acute treatment with the selective D-1 agonist, SKF 38393. The amount of the DARPP-32 dephospho-form measured by a back-phosphorylation assay was decreased by about 30% in agonist-treated animals. This effect was completely counteracted by the concomitant administration of the selective D-1 antagonist, SCH 23390, but not by a selective D-2 antagonist. This first demonstration of in vivo modulation of the phosphorylation state of DARPP-32 could, as a biochemical approach, represent a useful tool to gain further insight into the cascade of biochemical events elicited by specific dopaminergic drugs
Adenosine A(2) receptor agonist-induced neurotoxicity in rat cerebellar granule neurons
No full textAcute stimulation of A3 adenosine receptors has been shown to intensify damage in an in vivo model of global cerebral ischemia and to induce cell death in cell cultures. To investigate the mechanism for these cytotoxic phenomena, adenosine analogs of varied receptor subtype selectivities were applied directly to rat cerebellar granule neurons in culture. Agonists of A1, A(2A) and/or A(2B) receptors (CPA, NECA and CGS 21680) had no effect on neuronal survival during a 16 h incubation period. The highly selective adenosine A3 receptor agonist 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA) at ≤10 μM induced cell death in a concentration-dependent fashion. A structurally related nucleoside, cladribine, which has cytotoxic properties via a non-adenosine receptor related mechanism, had no effect on cell survival. Adding dbcAMP to the culture to activate cyclic AMP-dependent protein kinases attenuated Cl-IB-MECA-induced neurotoxicity, suggesting the Cl-IB-MECA-induced neuronal cell death is mediated by an inhibition of cyclic AMP production. Glutamate (50 μM) induced cell death to a degree comparable to that induced by 10 μM Cl-IB-MECA. Furthermore, a subcytotoxic concentration of Cl-IB-MECA (1 μM) significantly augmented glutamate neurotoxicity. In contrast, the adenosine A1/A2 agonists, the adenosine A1/A2 antagonist XAC, and the A(2A) antagonist SCH 58261 at micromolar concentrations had no effect on neuronal viability or on glutamate neurotoxicity. These results suggest that activation of adenosine A3 receptors may play an important role in regulating neuronal survival and death in cerebellar neurons
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