Eight G protein-coupled P2Y receptor subtypes respond to extracellular adenine and uracil mononucleotides and dinucleotides. P2Y receptors belong to the δ group of rhodopsin-like GPCRs and contain two structurally distinct subfamilies: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 (principally G q protein-coupled P2Y 1 -like) and P2Y 12-14 (principally G i protein-coupled P2Y 12 -like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 6 receptors induce vasodilation, while smooth muscle P2Y 2 , P2Y 4 , and P2Y 6 receptor activation leads to vasoconstriction. Pancreatic P2Y 1 and P2Y 6 receptors stimulate while P2Y 13 receptors inhibits insulin secretion. Antagonists of P2Y 12 receptors, and potentially P2Y 1 receptors, are anti-thrombotic agents, and a P2Y 2 /P2Y 4 receptor agonist treats dry eye syndrome in Asia. P2Y receptor agonists are generally pro-inflammatory, and antagonists may eventually treat inflammatory conditions. This article reviews recent developments in P2Y receptor pharmacology (using synthetic agonists and antagonists), structure and biophysical properties (using X-ray crystallography, mutagenesis and modelling), physiological and pathophysiological roles, and present and potentially future therapeutic targeting.Abbreviations: BMD, bone mineral density; DUSP, dual specificity protein phosphatase; ECL, extracellular loop; EPAC, exchange protein activated by cAMP; KO, knockout; MSD, musculoskeletal disorder; SNP, single nucleotide polymorphism; SS, Sjögren's syndrome; TM, transmembrane helix.
Diadenosine tetraphosphate (Ap4A) and diadenosine pentaphosphate (Ap5A) have been identified in bovine adrenal medullary tissue using an HPLC method. The values obtained were 0.1 +/- 0.05 mumol/g of tissue for both compounds. The subcellular fraction where Ap4A and Ap5A were present in the highest concentration was chromaffin granules: 32 nmol/mg of protein for both compounds (approximately 6 mM intragranularly). This value was 30 times higher than in the cytosolic fraction. Enzymatic degradation of Ap4A and Ap5A, isolated from chromaffin granules, with phosphodiesterase produces AMP as the final product. The Ap4A and Ap5A obtained from this tissue were potent inhibitors of adenosine kinase. Their Ki values relative to adenosine were 0.3 and 2 microM for Ap4A and Ap5A, respectively. The cytosolic fraction also contains enzymatic activities that degrade Ap4A as well as Ap5A. These activities were measured by an HPLC method; the observed Km values were 10.5 +/- 0.5 and 13 +/- 1 microM for Ap4A and Ap5A, respectively.
Previous work has established the presence of functional P2X 7 subunits in rat cerebellar astrocytes, which after stimulation with 3¢-O-(4-benzoyl)benzoyl ATP (BzATP) evoked morphological changes that were not reproduced by any other nucleotide. To further characterize the receptor(s) and signaling mechanisms involved in the action of BzATP, we have employed fura-2 microfluorometry and the patch-clamp technique. BzATP elicited intracellular calcium responses that typically exhibited two components: the first one was transient and metabotropic in nature -sensitive to phospholipase C inhibition and pertussis toxin treatment -, whereas the second one was sustained and depended on the presence of extracellular calcium. The ionotropic nature of this latter component was corroborated by measurements of Mn 2+ entry and macroscopic non-selective cation currents evoked by either BzATP (100 lM) or ATP (1 mM). The two components of the calcium response to BzATP differed in their pharmacological sensitivity. The metabotropic component was partially sensitive to pyridoxalphosphate-5¢-phosphate-6-azo-(-2-chloro-5-nitrophenyl)-2,4-disulfonate, a selective antagonist of P2Y 13 receptors, while the ionotropic component was modulated by external magnesium and markedly reduced by brilliant blue G and 3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methyl pyridine (A438079), thus implying the involvement of P2X 7 purinergic receptors. It is concluded that P2Y 13 and P2X 7 purinergic receptors are functionally expressed in rat cerebellar astrocytes and mediate the increase in intracellular calcium elicited by BzATP in these cells.
Abstract:We have examined the expression of mRNA for several P2Y nucleotide receptors by northern blot analysis in purified type 1 cerebellar astrocyte cultures. These results suggest that different P2Y subtypes could be responsible for ATP metabotropic calcium responses in single type 1 astrocytes. To identify these subtypes we have studied the pharmacological profile of ATP calcium responses using fura-2 microfluorimetry. All tested astrocytes responded to ATP and UTP stimulations evoking similar calcium transients. Most astrocytes also responded to 2-methylthioATP and ADP challenges. The agonist potency order was 2-methylthioATP Ͼ ADP Ͼ ATP ϭ UTP. Cross-desensitization experiments carried out with ATP, UTP, and 2-methylthioATP showed that 2-methylthioATP and UTP interact with different receptors, P2Y 1 and P2Y 2 or P2Y 4 . In a subpopulation of type 1 astrocytes, ATP prestimulation did not block UTP responses, and UDP elicited clear intracellular Ca 2ϩ concentration responses at very low concentrations. 2-MethylthioATP and UTP calcium responses exhibited different sensitivity to pertussis toxin and different inhibition patterns in response to P2 antagonists. The P2Y 1 -specific antagonist N 6 -methyl-2Ј-deoxyadenosine 3Ј,5Ј-bisphosphate (MRS 2179) specifically blocked the 2-methylthio-ATP responses. We can conclude that all single astrocytes coexpressed at least two types of P2Y metabotropic receptors: P2Y 1 and either P2Y 2 or P2Y 4 receptors. Moreover, 30 -40% of astrocytes also coexpressed specific pyrimidine receptors of the P2Y 6 subtype, highly selective for UDP coupled to pertussis-toxin insensitive G protein. Key Words: Astrocytes-Glial cells-ATP receptors-Nucleotide receptors-Calcium. J. Neurochem. 75, 2071Neurochem. 75, -2079Neurochem. 75, (2000.Neuropharmacologists have traditionally attributed most, if not all, of neurotransmitter effects to interactions with neuronal receptors. However, it has been clearly shown that glial cells express a large variety of neurotransmitter receptors, and a very active neuron-glia interaction is now considered the rule (McCarthy and Salm, 1991;Inagaki and Wada, 1994). In this sense, release of different components, including ATP and dinucleotides, from neurons and other surrounding cells can affect astrocyte functions, and, vice versa, ATP released from astrocytes can modulate other cellular types in the nervous system (Verkhratsky et al., 1998;Guthrie et al., 1999).The extracellular actions of nucleotides are mediated through specific membrane purinergic receptors termed P2 purinoceptors, which have been classified in two types, ionotropic P2X and metabotropic P2Y receptors. They differ in their pharmacological profile, transduction mechanism, and molecular structure (Ralevic and Burnstock, 1998). Both subtypes are present in different neurons and glial cells (Evans et al., 1992;Salter and Hicks, 1994;Kirischuk et al., 1995;Bernstein et al., 1996;Mateo et al., 1998). Most P2Y receptors activate phospholipase C, leading to the formation of inositol triphosphate ...
Background: Purinergic P2X7 receptors regulate proliferation, differentiation, and cell death in both the CNS and non-CNS tissues.Results: Sp1 factor activates the P2rx7 promoter. This regulation is abolished by SP1 binding sites mutation, Sp1 knockdown, and mithramycin A treatment.Conclusion: Sp1 regulates the expression of P2X7 receptor.Significance: Learning how P2X7 expression is controlled is crucial for understanding P2X7-mediated brain processes in health and disease.
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