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At least 19 recordsLinked to original sources
PubMed1997

Differential effects of thiopental on neuronal nicotinic acetylcholine receptors and P2X purinergic receptors in PC12 cells.

BACKGROUND: PC12 cells, derived from rat pheochromocytoma, express neuronal nicotinic acetylcholine receptors (nAchRs) and P2X purinergic receptors, both of which resemble the receptors in postganglionic sympathetic neurons. The former is the established and the latter is the putative receptor to mediate fast synaptic transmission. The authors investigated effects of thiopental on these two ligand-gated ion channels. METHODS: Whole cell currents were recorded in PC12 cells without treatment of nerve growth factor, using conventional whole cell patch clamp technique. Nicotine or adenosine triphosphate (ATP) 30 microM was applied for 4-5 s in the absence or presence of thiopental 3-300 microM. RESULTS: Nicotine induced the rapidly decaying inward current at -60 mV, which exhibited the characteristics of the neuronal nAchR-mediated current. Thiopental inhibited the nicotine-induced inward current and accelerated the current decay in a dose-dependent manner, resulting in the greater effects on the steady current than the peak current. IC50s for the peak and steady current were 56.7 and 7.4 microM, when the anesthetic was coapplied with nicotine. Thiopental's inhibition was not associated with a change in the reversal potential and was voltage-independent at membrane potential of -30 to -70 mV. Most of thiopental's effects seemed to require channel opening. In contrast to the nicotine-induced current, thiopental had little effect on the current elicited by ATP. CONCLUSIONS: Thiopental, whose reported EC50 for general anesthesia is 25 microM, inhibited the neuronal nAchR-mediated current but not the P2X receptor-mediated response in PC12 cells at clinically relevant concentrations. Inhibition may result in suppression of synaptic transmission in sympathetic ganglia.

Adenosine Triphosphate↗
PubMed1991

Solubilization of a guanine nucleotide-sensitive form of the P2Y-purinergic receptor.

P2Y-Purinergic receptors were solubilized from turkey erythrocyte plasma membranes with the nonionic detergent digitonin. Adenosine 5'-O-(2-[35S]thiodiphosphate) ([35S]ADP beta S) labeled a single population of soluble high affinity sites (Kd = 12.9 nM; Bmax = 4.5 pmol/mg of protein) in an equilibrium binding assay; adenine nucleotide analogs competitively inhibited [35S]ADP beta S binding with a rank order of potency consistent with that for P2Y-purinergic receptors. Radioligand binding to solubilized P2Y-purinergic receptors was noncompetitively inhibited by guanine nucleotides with a rank order of potency that was in agreement with the potency order observed for guanine nucleotide-mediated inhibition of [35S]ADP beta S binding in purified turkey erythrocyte plasma membranes. The rate constant for dissociation of [35S]ADP beta S from solubilized receptors was increased 2.3-fold by guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S). Plasma membrane P2Y-purinergic receptors were labeled with [35S]ADP beta S or covalently labeled with the photoaffinity probe 3'-O-(4-benzoyl)benzoyl adenosine 5'-[alpha-32P]triphosphate ([alpha-32P]BzATP) before solubilization and gel filtration chromatography on Superose 12. [35S]ADP beta S- or [alpha-32P]BzATP-labeled species eluted as a single peak of radioactivity of apparent Mr greater than or equal to 300,000. Incubation of the Mr greater than or equal to 300,000 protein species with GTP gamma S before rechromatography resulted in loss of labeling of proteins by [35S]ADP beta S and a shift in apparent size of the covalently [alpha-32P]BzATP-labeled species to a single peak of radioactivity of approximate Mr 70,000. These results suggest that a P2Y-purinergic receptor-guanine nucleotide regulatory protein complex is stable to membrane solubilization with digitonin, even in the absence of prebound agonist.

Adenine↗
PubMed2003

Activation of purinergic receptor subtypes modulates odor sensitivity.

Purinergic nucleotides, including ATP and adenosine, are important neuromodulators of peripheral auditory and visual sensory systems (Thorne and Housley, 1996). ATP released by the olfactory epithelium (OE) after noxious stimuli provides a physiological source for a neuromodulatory substance independent of efferent innervation. Here we show that multiple subtypes of purinergic receptors are differentially expressed in olfactory receptor neurons and sustentacular support cells. Activation of purinergic receptors evoked inward currents and increases in intracellular calcium in cultured mouse olfactory receptor neurons. A mouse olfactory epithelial slice preparation and confocal imaging were used to measure changes in intracellular calcium in response to odors, purinergic receptor (P2R) agonists, or combined odor + P2R agonists. Pharmacological studies show that both P2Y and P2X receptor activation by exogenous and endogenous ATP significantly reduces odor responsiveness. Moreover, purinergic receptor antagonists increase the odor-evoked calcium transient, providing direct evidence that endogenous ATP modulates odor sensitivity via activation of multiple purinergic receptor subtypes in olfactory receptor neurons. Odor activation of G-protein-coupled receptors results in increased cAMP production, opening of cyclic nucleotide-gated channels, influx of Ca2+ and Na+, depolarization of the membrane, and activation of voltage- and Ca2+-gated ion channels. On-cell current-clamp recordings of olfactory receptor neurons from neonatal mouse slices revealed that ATP reduced cyclic nucleotide-induced electrical responses. These data also support the idea that ATP modulates odor sensitivity in mammalian olfactory neurons. Peripheral ATP-mediated odor suppression is a novel mechanism for reduced olfactory sensitivity during exposure to olfactotoxins and may be a novel neuroprotective mechanism.

Adenosine Diphosphate↗
PubMed1992

K562 leukemia cells express P2T (adenosine diphosphate) purinergic receptors.

The P2T purinergic receptor for ADP has previously been found only in platelets. We investigated the effect of ADP on the concentration of intracellular free calcium ([Ca++]i) in fura-2-loaded K562 leukemia cells, a cell line with the potential for megakaryocytic differentiation. ADP causes a rapid and transient increase in [Ca++]i, which peaks within 5 to 10 sec. The EC50 for this response is 0.4 microM. A major portion of the increased calcium is due to mobilization of intracellular stores because the response to ADP is only partially reduced in the absence of extracellular calcium. Exposure to ADP desensitizes K562 cells to additional administrations of this nucleotide. Pretreatment of K562 cells with the protein kinase C activator phorbol 12-myristate 13-acetate completely blocks the response to ADP. This effect of phorbol 12-myristate 13-acetate is prevented by the protein kinase C inhibitor staurosporine, but staurosporine does not affect the progression of desensitization after repeated ADP exposures. ATP does not increase [Ca++]i in K562 cells, but antagonizes the response to ADP. We propose that the P2T receptor for ADP in K562 cells is an early marker for megakaryocytic differentiation. Furthermore, this immortalized nucleated cell line may be a useful model to decipher the signal transduction pathways involved in the ADP response.

Adenosine Diphosphate↗
PubMed2000

Expression of purinergic receptors in bipolar cells of the rat retina.

P2X receptors are ligand-gated ion channels which are activated by excitatory neurotransmitter ATP. Despite considerable evidence of signaling by extracellular nucleotides in other sensory systems, P2X receptors in the visual system have only rarely been studied, and almost nothing is known about their functional significance in the retina. To determine whether ATP plays a role in the modulation of vertical retinal signal pathways, we examined the expression of P2X receptor mRNA in freshly isolated bipolar cells of the rat retina (Brown Norway, P25) using the single-cell RT-PCR technique. Positive amplification signals were found in about 33% of the bipolar cells for P2X(3), P2X(4) and P2X(5) but not for P2X(7) mRNA. We conclude that at least a subpopulation of bipolar cells in the rat retina expresses ionotropic P2 receptors of the P2X type and that these possibly exert a neuromodulatory influence on information processing in the retina.

Animals↗
PubMed2000

Evidence for P2X(3), P2X(4), P2X(5) but not for P2X(7) containing purinergic receptors in Müller cells of the rat retina.

P2X receptors are ligand-gated ion channels activated by ATP. They are expressed in a broad variety of tissues. To date, eight P2X receptor subunits (P2X(1)-P2X(7), P2XM) have been cloned. In spite of the considerable evidence of signaling by extracellular nucleotides in other sensory systems, only few studies have been undertaken in the retina. In earlier studies, we have demonstrated that there is mRNA expression of the P2X(2-5) and P2X(7) subunits in the rat retina. In the present study, molecular biological methods were used to investigate expression of P2X receptor mRNA in freshly isolated Müller cells (MCs) of the adult rat retina (Brown Norway). A total of 36 MCs was analyzed, employing the single-cell RT-PCR. A positive amplification signal of 11/14 for P2X(3)-mRNA, 5/10 for P2X(4)-mRNA, 3/10 for P2X(5)-mRNA and 0/8 for P2X(7)-mRNA was revealed. Additionally, the astroglial identity of the cells under studied was confirmed in 10 cases by simultaneous amplification of RT-PCR products of glutamine synthetase (GS)- and P2X-mRNA. We conclude that MCs of rat retina express ionotropic P2 receptors, which, in addition to other functions, may play a key role within the recently described long range calcium signaling and the fast direct glia-neuron interactions in the rat retina.

Animals↗
PubMed2003

Purinergic receptors are part of a signaling system for keratinocyte proliferation, differentiation, and apoptosis in human fetal epidermis.

We have investigated the expression of P2X5, P2X7, P2Y1, and P2Y2 receptor subtypes in 8- to 11-wk-old human fetal epidermis in relation to markers of proliferation (proliferating cell nuclear antigen (PCNA) and Ki-67), keratinocyte differentiation (cytokeratin K10 and involucrin), and markers of apoptosis (TdT-mediated dUTP nick end labeling (TUNEL) and anti-caspase-3). Immunohistochemistry showed that each of the four receptors was expressed in spatially distinct zones of the developing epidermis: P2Y1 receptors were found in the basal layer, P2X5 receptors were predominantly in the basal and intermediate layers, and both P2Y2 and P2X7 receptors were in the periderm. Colocalization experiments suggested different functional roles for these receptors. P2Y1 receptors were found in fetal keratinocytes positive for PCNA and Ki-67, suggesting a role in proliferation. P2X5 receptors double labeled with differentiated fetal keratinocytes that were positive for cytokeratin K10, suggesting a role in differentiation. P2X7 receptors colocalized with anti-caspase-3 antibody and were also expressed in periderm cells positive for TUNEL, suggesting a role in periderm cell apoptosis. P2Y2 receptors were found only in periderm cells and may have a role in chloride and fluid secretion into the amniotic fluid.

Apoptosis↗
PubMed2002

P2X purinergic receptor channel expression and function in bovine aortic endothelium.

We examined bovine aortic endothelial cells (BAECs) for the functional expression of P2X receptors, the ATP-gated cation channels. We identified the P2X subtypes present in BAECs using RT-PCR. mRNA was present for only three of seven family members: P2X4, P2X5, and P2X7. We then characterized agonist-activated currents in whole cell and outside-out patch recordings using 2-methyl-thio-ATP (MeSATP) as a P2X4 and P2X5 receptor agonist and 2',3'-O-(4-benzoylbenzoyl)ATP (BzATP) as a P2X7 receptor agonist. MeSATP (10-20 microM) produced current with characteristics of P2X4 receptors. The current was an inwardly rectifying current, reversed near 0 mV, slowly desensitized, was not blocked by suramin (300 microM) or reactive blue (60 microM), and had a single channel conductance of 36 pS. BzATP (10-100 microM), on the other hand, activated a 9-pS channel with sustained activity in the continued presence of the agonist. BzATP-activated current was blocked by reactive blue (60 microM) and by suramin (approximately 50% block at 300 microM). We confirmed, by immunocytochemistry, the presence of P2X4 and P2X7 protein. The agonists failed, however, to induce significant uptake of the large molecule YO-PRO, indicating the lack of pore development that has been demonstrated for P2X7 and P2X4 in response to agonist in some cell types.

Adenosine Triphosphate↗
PubMed1994

Mobilization of intracellular Ca2+ by adenine nucleotides in human T-leukaemia cells: evidence for ADP-specific and P2y-purinergic receptors.

The expression of purinergic receptors on human T-cells was investigated and the receptors were shown to be functionally coupled to intracellular signals in two out of eight T-leukaemia cell-lines. Addition of adenine nucleotides resulted in mobilization of intracellular Ca2+ in HPB-ALL cells and a cell line (CB1) recently isolated from a patient with T-acute lymphoblastic leukaemia. Of a range of nucleotides tested only ADP and ATP elevated intracellular levels of Ca2+, with ADP being the more potent agonist. Ca2+ mobilization by ATP was accompanied by increased inositol phosphate production and was blocked by the purinergic receptor antagonist, Reactive Blue 2, indicating that ATP was interacting with a P2y receptor. Intracellular Ca2+ release triggered by ADP was independent of both inositol phosphate production and protein tyrosine phosphorylation. Expression of the transmembrane phosphotyrosine phosphatase, CD45, had no effect on ADP-stimulated Ca2+ mobilization. Our results show that functional P2y receptors can be expressed on T-cells, and also identify a novel T-cell ADP receptor. Signals mediated by these purinergic receptors could play important roles in modulating T-cell function.

Adenosine Diphosphate↗
PubMed2005

Purinergic receptor modulation of BV-2 microglial cell activity: potential involvement of p38 MAP kinase and CREB.

ATP is abundant in the extracellular fluid following brain injury, and it exerts potent modulatory effects on microglia, whose hyperactivation is thought to exacerbate neuronal damage. We show here that ATP decreases LPS-stimulated iNOS and COX-2 expression and reduces NO release in BV-2 microglia by a mechanism involving p38 MAP kinase. Further, we demonstrate that the inhibitory effects of ATP on NO production occur within 30 min of exposure and correlate with activation of the transcription factor CREB. Together, these data suggest that ATP may exert neuroprotective effects in the brain via a mechanism involving augmented activation of the p38/CREB pathway.

Adenine Nucleotides↗
PubMed2002

Expression, regulation, and function of P2X(4) purinergic receptor in human cervical epithelial cells.

Micromolar concentrations of ATP stimulate biphasic change in transepithelial conductance across CaSki cultures on filters, an acute transient increase (phase I response; triggered by P2Y(2) receptor and mediated by calcium mobilization-dependent cell volume decrease) followed by a slower decrease in permeability (phase II response). Phase II response is mediated by augmented calcium influx and protein kinase C-dependent increase in tight junctional resistance. The objective of the study was to determine the role of P2X(4) receptor as a mediator of phase II response. Human cervical epithelial cells express P2X(4) receptor mRNA (1.4-, 2.2-, and 4.4-kb isoforms by Northern blot analysis) and P2X(4) protein. Depletion of vitamin A reversibly downregulated P2X(4) receptor mRNA and protein and ATP-induced calcium influx. Depletion of vitamin A abrogated phase II response, and the effect could be partially reversed only with retinoic acid receptor (RAR)-selective retinoids but not retinoid X receptor (RXR) agonists. Depletion of vitamin A also abrogated protein kinase C increase in tight junctional resistance, and the effect could not be reversed with retinoids. Depletion of vitamin A also abrogated phase I increase in permeability and reversibly downregulated P2Y(2) receptor mRNA and ATP-induced calcium mobilization. However, in contrast to phase II response, both RAR and RXR agonists could fully reverse those effects. These results suggest that phase II response is mediated by a P2X(4) receptor mechanism.

Adenosine Triphosphate↗
PubMed1994

Expression of a cloned P2Y purinergic receptor that couples to phospholipase C.

P2Y purinergic receptors previously have been shown to couple either to activation of phospholipase C through a pertussis toxin-insensitive mechanism or to inhibition of adenylyl cyclase through pertussis toxin-sensitive members of the G1 family of G proteins. These and other pharmacological data strongly suggest that multiple P2Y purinergic receptors exist. Webb et al. [FEBS Lett. 324:219-225 (1993)] cloned a cDNA that, when expressed in frog oocytes, displayed the general pharmacological characteristics of a P2Y purinergic receptor but whose second messenger linkage was not resolved. We have now cloned the meleagrid (turkey) homologue of the previously cloned chick P2Y purinergic receptor and have stably expressed it in a heterologous human cell line (1321N1 astrocytoma cells) to establish its signaling properties. The purinergic receptor agonist 2-methylthio-ATP (2MeSATP) stimulated a marked activation of phospholipase C in 1321N1 cells stably expressing the meleagrid receptor. The order of potency of a series of analogues of ATP and ADP for stimulation of phospholipase C by the receptor expressed in 1321N1 cells [2MeSATP = 2-methylthio-ADP > adenosine 5'-O-(2-thio)diphosphate > ADP > 2-chloro-ATP = adenosine 5'-O-(3-thio)triphosphate > or = ATP > adenylyl-imidodiphosphate > UTP] was similar to that observed for P2Y purinergic receptors in turkey erythrocytes and many other tissues and was markedly different from those of the P2U and P2X purinergic receptor subtypes. Stimulation of inositol lipid hydrolysis by P2Y purinergic agonists was not affected by preincubation of cells with pertussis toxin. In contrast to its marked effects on phospholipase C activity, 2MeSATP caused only a small and variable inhibition of cAMP accumulation. Ribonuclease protection analysis of turkey tissues showed that this P2Y purinergic receptor is most highly expressed in blood and brain. Taken together, these results indicate that a phospholipase-C-activating P2Y purinergic receptor has been cloned and stably expressed in 1321N1 astrocytoma cells.

Animals↗
PubMed2006

Distinct roles for protein kinase C isoforms in regulating platelet purinergic receptor function.

ADP is a critical regulator of platelet activation, mediating its actions through two G protein-coupled receptors (GPCRs), P2Y1 and P2Y12. We have shown previously that the receptors are functionally desensitized, in a homologous manner, by distinct kinase-dependent mechanisms in which P2Y1 is regulated by protein kinase C (PKC) and P2Y12 by G protein-coupled receptor kinases. In this study, we addressed whether different PKC isoforms play different roles in regulating the trafficking and activity of these two GPCRs. Expression of PKCalpha and PKCdelta dominant-negative mutants in 1321N1 cells revealed that both isoforms regulated P2Y1 receptor signaling and trafficking, although only PKCdelta was capable of regulating P2Y12, in experiments in which PKC was directly activated by the phorbol ester phorbol 12-myristate 13-acetate (PMA). These results were paralleled in human platelets, in which PMA reduced subsequent ADP-induced P2Y1 and P2Y12 receptor signaling. PKC isoform-selective inhibitors revealed that novel, but not conventional, isoforms of PKC regulate P2Y12 function, whereas both novel and classic isoforms regulate P2Y1 activity. It is also noteworthy that we studied receptor internalization in platelets by a radioligand binding approach showing that both receptors internalize rapidly in these cells. ADP-induced P2Y1 receptor internalization is attenuated by PKC inhibitors, whereas that of the P2Y12 receptor is unaffected. Both P2Y1 and P2Y12 receptors can also undergo PMA-stimulated internalization, and here again, novel but not classic PKCs regulate P2Y12, whereas both novel and classic isoforms regulate P2Y1 internalization. This study therefore is the first to reveal distinct roles for PKC isoforms in the regulation of platelet P2Y receptor function and trafficking.

Animals↗
PubMed2006

Purinergic receptors involved in the immunomodulatory effects of ATP in human blood.

We recently showed that the physiological compound ATP simultaneously inhibited TNF-alpha and stimulated IL-10 release in LPS-PHA stimulated blood. The purpose of the present study was to determine the mechanism involved in the concerted modulatory effect of ATP on TNF-alpha and IL-10. Incubation of blood with ATP in the presence of selective P2 receptor antagonists showed that the stimulatory effect of ATP on IL-10 release was completely annihilated by both 2-MeSAMP (a P2Y12/13 receptor antagonist) and PSB-0413 (a P2Y12 receptor antagonist). On the other hand, the inhibitory effect of ATP on TNF-alpha release was completely reversed by 5'-AMPS (a P2Y11 receptor antagonist) as well as by H-89, an inhibitor of cAMP-activated PKA. The concerted inhibition by ATP of TNF-alpha release via P2Y11 activation and stimulation of IL-10 release via P2Y12 activation implicates a novel approach towards immunomodulation by altering the balance among pro- and anti-inflammatory cytokines.

Adenosine Triphosphate↗
PubMed2005

Regulation of ion transport via apical purinergic receptors in intact rabbit airway epithelium.

We investigated purinergic receptors involved in ion transport regulation in the intact rabbit nasal airway epithelium. Stimulation of apical membrane P2Y receptors with ATP or UTP (200 microM) induced transient increases in short-circuit current (Isc) of 13 and 6% followed by sustained inhibitions to 8 and 17% below control level, respectively. Serosal application of nucleotides had no effect. The ATP-induced response appeared to involve additional activation of apical adenosine (P1) and P2X receptors. The inhibitory effect of ATP and UTP on Isc was eliminated by pretreatment with amiloride (100 microM), while the stimulatory effect was potentiated, indicating that ATP and UTP inhibit Na+ and stimulate Cl- current. Ionomycin (1 microM) induced responses similar to UTP and ATP and desensitized the epithelium to the nucleotides, indicating involvement of intracellular Ca2+ (Ca2+ i. Furthermore, ATP, UTP and ionomycin induced 21, 24, and 21% decreases, respectively, in transepithelial conductance. Measurements of unidirectional isotope fluxes showed a 39% decrease in the dominant net Na+ absorption in response to ATP, while the smaller net Cl- secretion increased only insignificantly and unidirectional Cl- fluxes decreased significantly. The results suggest that nucleotides released to the airway surface liquid exert an autocrine regulation of epithelial NaCl absorption mainly by inhibiting the amiloride-sensitive epithelial Na+ channel (ENaC) and paracellular anion conductance via a P2Y receptor-dependent increase in Ca2+ i, while stimulation of Cl- secretion is of minor importance.

Adenosine↗
PubMed1993

Functional expression and photoaffinity labeling of a cloned P2U purinergic receptor.

ATP and UTP can function as extracellular signaling molecules by activating plasma membrane receptors termed P2 purinergic receptors. In the present study a P2U receptor cDNA has been expressed in K-562 human leukemia cells, one of the few available mammalian cell lines that lacks an endogenous P2U receptor. In stably transfected cells, low micromolar concentrations of ATP or UTP activated the receptor, resulting in the mobilization of intracellular calcium but not the influx of extracellular calcium. A photoaffinity agonist of the P2U receptor, 3'-O-(4-benzoylbenzoyl)adenosine 5'-[alpha-32P]triphosphate ([alpha-32P]BzATP), photolabeled several proteins in plasma membranes from the stable transfectant or from untransfected K-562 cells. The photolabeling of a 53-kDa protein was significantly greater in plasma membranes from the stable transfectant than from untransfected cells. A mutant receptor containing six consecutive histidine residues at its carboxyl terminus was constructed and used to verify that this 53-kDa protein was the P2U receptor. In plasma membranes from cells expressing the histidine-tagged P2U receptor, but not from cells expressing the wild-type receptor, a single [alpha-32P]BzATP-labeled protein with a molecular mass of 53 kDa was retained on a Ni(2+)-charged Sepharose column, which binds many proteins containing a polyhistidine tag. Photolabeling of the 53-kDa protein by [alpha-32P]BzATP was inhibited by ATP but not by UTP, raising the possibility that the P2U receptor may have distinct binding sites for each nucleotide.

Adenosine Triphosphate↗
PubMed2002

Nonselective cation conductance activated by muscarinic and purinergic receptors in rat spiral ganglion neurons.

The present study characterizes the ionic conductances activated by acetylcholine (ACh) and ATP, two candidate neuromodulators, in isolated spiral ganglion neurons (SGNs). Brief application (1 s) of ACh evoked in a dose-dependent manner (EC(50) = 4.1 microM) a reversible inward current with a long latency (average 1.3 s), at holding potential (V(h)) = -50 mV. This current was reversibly blocked by atropine and mimicked by muscarine. Application of ATP also evoked a reversible inward current at V(h) = -50 mV, but the current showed two components. A fast component with a short latency was largely reduced when N-methyl-D-glucamine (NMDG) replaced extracellular sodium, implying a P2X-like ionotropic conductance. The second component had a longer latency (average 1.1 s) and was presumably activated by metabotropic P2Y-like receptors. The second component of ATP-evoked current shared similar characteristics with the responses evoked by ACh: the current reversed near 0 mV, displayed inward rectification, could be carried by NMDG, and was insensitive to extracellular and intracellular calcium. This ACh-/ATP-evoked conductance was reversibly inhibited by preapplication of ionomycin. These results suggest that muscarinic receptors and purinergic metabotropic receptors activate a similar large nonselective cation conductance via a common intracellular pathway in SGNs, a candidate mechanism to regulate neuronal excitability of SGNs.

Acetylcholine↗
PubMed1997

Effects of extracellular ATP and adenosine on different thymocyte subsets: possible role of ATP-gated channels and G protein-coupled purinergic receptor.

To explore the possible role of purinergic receptors in thymocyte development and in pathogenesis of adenosine deaminase SCID, we studied effects of extracellular adenosine triphosphate (ATP(ext)) and adenosine on TCR- and steroid hormone-triggered processes in mouse thymocytes. Reverse transcriptase-PCR analysis confirms the mRNA expression of several types of purinergic receptors, while the functioning of ATP receptors in thymocytes is reflected by ATP(ext)-induced intracellular calcium increases and by thymocyte subset-specific sensitivity to the effects of ATP(ext) and adenosine. Only ATP(ext), but not the ATP catabolites, adenosine, dexamethasone, or TCR cross-linking, was efficient in triggering rapid protein synthesis independent lysis of CD4+8- thymocytes and peripheral CD4+ T cells. In contrast, extracellular adenosine specifically induced the apoptosis of CD4+8+ thymocytes. ATP(ext) also induced a slower process of DNA fragmentation and protein synthesis-dependent apoptosis in all thymocyte subsets. ATP(ext) had an additive effect with TCR cross-linking in the induction of thymocyte death, but, unexpectedly, the effects of ATP(ext) at high concentration were antagonistic to steroid-induced apoptosis. Described here, the properties of ATP(ext) and adenosine are consistent with their involvement in the regulation of T cell development due to differential expression and signaling through purinergic receptors in different thymocyte subsets. The possible role of purinergic receptor signaling in T cell differentiation and adenosine deaminase SCID is discussed.

Adenosine↗