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UTP as an Extracellular Signaling Molecule

Eduardo R. Lazarowski and Richard C. Boucher

E. R. Lazarowski and R. C. Boucher are at the School of Medicine, Department of Medicine, The Cystic Fibrosis Treatment and Research Center, University of North Carolina, Chapel Hill, NC 27599-7248.

	Abstract

 
In addition to their central role in many biochemical processes, uridine nucleotides are important extracellular signaling molecules that regulate a broad spectrum of cell functions via activation of P2Y₂, P2Y₄, and P2Y₆ receptors. Cellular release of UTP provides a mechanism for autocrine control of calcium- or protein kinase C–dependent processes.

	Introduction

Top Introduction Receptors for uridine... Measurement of UTP in... Basal and stimulated release... Autocrine regulation of P2Y... Physiological role of nucleotide... Conclusions References

 
The identification of two families of receptors for extracellular nucleotides, the ionotropic P2X and the metabotropic P2Y receptors (4), suggested that 5'-nucleotide triphosphates (ATP and UTP) that were thought to serve exclusively subcellular metabolic functions also play important extracellular signaling roles. The reported presence in most tissues of ectoenzymes that rapidly degrade extracellular ATP provided additional support to the notion that regulated processes for the release and control of extracellular nucleotide concentrations may exist. Numerous studies focused on extracellular ATP are consistent with these assumptions. ATP, stored in specialized compartments in nerve terminals, chromaffin cells, mast cells, and circulating platelets, is released during secretory events to regulate a variety of cell responses, including smooth muscle contraction, thrombus formation, and inflammation. ATP release from nonsecretory tissues (e.g., hypoxia, shear stress) has also been extensively documented (for review, see Ref. 7).

In contrast to the compelling evidence for the extracellular signaling role of ATP, the hypothesis that UTP may also fulfill an autocrine/paracrine role has only recently gained experimental support. The development of sensitive methodologies that allow quantification of UTP has improved our understanding of the role of extracellular uridine nucleotides. This review discusses recent findings supporting the concept that release of cellular UTP is a physiologically relevant signaling process.

	Receptors for uridine nucleotides

Top Introduction Receptors for uridine... Measurement of UTP in... Basal and stimulated release... Autocrine regulation of P2Y... Physiological role of nucleotide... Conclusions References

 
The notion that UTP may function as an extracellular messenger originated from the identification of a subset of P2Y receptors that recognize uridine nucleotides as their most potent and, in some cases, exclusive agonists. P2Y receptors are members of the large family of G protein-coupled receptors, and they include five functionally characterized human gene products, three of which are activated by uridine nucleotides (Fig. 1). The P2Y₂ receptor, originally called P_2U purinoceptor, recognizes both ATP and UTP as the most potent agonists. The human P2Y₄ and P2Y₆ receptors were recently identified and characterized as UTP- and UDP-selective receptors, respectively (Fig. 1). Uridine nucleotide-recognizing P2Y receptors share an ~40% identity of predicted overall amino acid sequences, with higher homology within the putative seven transmembrane (TM) domains, mostly in TM III, TM IV, and TM VII.

View larger version (32K): [in this window] [in a new window]   FIGURE 1. The P2Y receptor subfamily. Five human G protein-coupled P2Y receptors have been identified at the molecular level. The predicted 328- to 375-amino acid gene products display higher homology within their putative 7-transmembrane domains. The most potent naturally occurring adenine and uridine nucleotides acting on each P2Y receptor are indicated on the left.

View larger version (17K): [in this window] [in a new window]   FIGURE 2. Schematic representation of the signaling pathways activated by extracellular uridine nucleotides. MAPK, mitogen-activated protein kinase; PLA2, phospholipase A2; PLC, phospholipase C; PKC, protein kinase C; IP3, inositol 1,4,5-triphosphate.

Highly selective uridine nucleotide responses (i.e., UTP, UDP >> ATP) that could not be explained by activation of the P2Y₂ receptor have also been reported in various rat tissues. UTP and/or UDP promote activation of phospholipases C and A₂ in rat macrophages and in rat C6-2B glioma cells, stimulate the neural release of catecholamines, regulate the vascular tone of intrapulmonary arteries, and promote activation and proliferative responses in smooth muscle cells. These effects of uridine nucleotides were not mimicked by adenine nucleotides and likely reflect activation of P2Y₄ or P2Y₆ receptors.

	Measurement of UTP in biological samples

Top Introduction Receptors for uridine... Measurement of UTP in... Basal and stimulated release... Autocrine regulation of P2Y... Physiological role of nucleotide... Conclusions References

 
Direct evidence for the role of UTP and UDP as endogenous agonists for P2Y receptors requires the demonstration of their cellular release in quantities sufficient to trigger receptor activation. However, difficulties in sampling the extracellular surface liquid layer without disrupting the relevant environment at the cell surface limit our capacity to measure extracellular nucleotide concentrations in situ, and hydrolysis and bulk dilutions are major limitations for the accurate quantification of nucleotides in biological fluids. Moreover, attempts to measure the concentration of extracellular UTP have been hampered, until recently, by the lack of a highly sensitive method of detection.

Cellular release of uridine nucleotides was first reported by Saiag et al. (13), who observed in studies with [³H]uridine-loaded bovine vascular endothelial cells that changes in perfusion rates resulted in increased accumulation of extracellular [³H]UTP. An enzymatic assay, which allowed quantification of physiologically relevant concentrations of UTP, was subsequently devised on the basis of the high selectivity of UDP-glucose pyrophosphorylase for UTP. UDP-glucose pyrophosphorylase is a key enzyme in the metabolic pathway for the synthesis of glycogen. In the presence of UTP, UDP-glucose pyrophosphorylase catalyzes the uridinylation of glucose-1P in a reaction that results in the formation of UDP-glucose and inorganic pyrophosphate. Using [¹⁴C]glucose-1P as the tracer substrate, the UTP-dependent conversion of [¹⁴C]glucose-1P to [¹⁴C]UDP-glucose could be quantitatively measured by HPLC with a sensitivity for UTP in the low nanomolar range, i.e., 1 nM (10).

	Basal and stimulated release of UTP

Top Introduction Receptors for uridine... Measurement of UTP in... Basal and stimulated release... Autocrine regulation of P2Y... Physiological role of nucleotide... Conclusions References

 
The concentration of UTP measured in the medium bathing ~3 x 10⁵ tissue culture cells under basal conditions rangwed from 1 to 5 nM and represented approximately one-third of the ATP concentration. Because ectonucleotidase activities exist in the face of stable concentrations of UTP and ATP in the medium of resting cells, a mechanism for the basal ("constitutive") release of nucleotides likely exists, which balances hydrolysis. As discussed below, constitutive release of UTP may provide a basal tone for P2Y₂, P2Y₄, and P2Y₆ receptors in resting cells.

Human platelets constitute the only tissue in which regulated release of UTP has been documented (10). Addition of thrombin to washed platelets that were kept in suspension in a physiological cell number resulted in a rapid, 10-fold increase of extracellular UTP, which reached concentrations capable of stimulating P2Y₂ or P2Y₄ receptors. Although UTP is not an agonist on human platelets, one speculation is that UTP released from activated platelets during thrombus formation may stimulate subsets of uridine nucleotide receptors on neighboring vascular endothelial and smooth muscle cells, promoting trophic responses during tissue recovery.

Mechanical stress appeared to be the major, if not the only, stimulus for cytosolic UTP release in nonsecretory tissues. Shear forces applied on perfused bovine endothelial cells resulted in the release of cellular UTP (13). Similarly, mechanical stimulation of 1321N1 human astrocytoma cells resulted in a 10- to 20-fold increase in extracellular UTP concentrations (10). These observations were recently extended to other neural cells (e.g., C6 glioma cells and primary astrocytes) and nonneural cells (e.g., airway and intestinal epithelial cells) (10). UTP release from these cells seemed to follow the same pattern of ATP release: 1) both nucleotides were released with similar time courses, and 2) extracellular accumulation of UTP and ATP appeared to reflect their relative intracellular levels.

The observation that the ratio of UTP to ATP released into the medium parallels that of the cell content suggests that the release mechanism does not discriminate between these two molecules. Several mechanisms have been proposed to account for the mechanical release of cytosolic ATP, which may apply also for UTP release. These putative mechanisms include stretch-activated channels, ATP-binding cassette (ABC) transporters, and gap junction-type hemichannels. A proposed role for the cystic fibrosis transmembrane regulator (CFTR), a member of the ABC transporter family, in the release of cytosolic ATP was not substantiated in experiments in which ATP was either directly or indirectly measured in the medium bathing cells overexpressing CFTR as well as in studies comparing normal and CFTR-defective (CF) epithelial cells (see Refs. 14 and references therein). Since no differences in luminal UTP concentrations were found between normal and CF cells under either resting or mechanically stimulated conditions (10), it is also unlikely that CFTR was involved in UTP release by airway epithelial cells. Aside from these largely descriptive studies, little is known about the mechanism and pathways involved in the release of UTP (and ATP) from nonsecretory cells.

	Autocrine regulation of P2Y receptors

Top Introduction Receptors for uridine... Measurement of UTP in... Basal and stimulated release... Autocrine regulation of P2Y... Physiological role of nucleotide... Conclusions References

 
The signaling role of released UTP was recently demonstrated in vitro (11). Mechanical stimulation of the human P2Y₄ receptor-expressing 1321N1 human astrocytoma cells resulted in the accumulation of inositol phosphates and mobilization of intracellular calcium. Responses to shear stress were dependent on P2Y₄ receptor expression, i.e., no such responses were observed with wild-type or "empty" vector-infected 1321N1 cells that did not express endogenous receptors for nucleotides. Because 1) UTP is the only nucleotide that activates the human P2Y₄ receptor and 2) the effect of shear on calcium responses was abolished by removing UTP from the medium with apyrase, these observations provided experimental support for an autocrine role of released UTP. In the same study, it was also demonstrated that the basal accumulation of inositol phosphates, i.e., in resting cells, was reduced 30% by the addition of apyrase, also providing the first evidence that constitutive release of UTP confers P2Y₄ receptor-promoted phospholipase C activity to resting cells.

The autocrine role of released nucleotides was also demonstrated in airway epithelial cells. Studies with fura 2-loaded polarized cultures of both primary human nasal epithelial cells and immortalized mouse nasal epithelial cells that express an endogenous P2Y₂ receptor showed that mechanical deformation of the apical surface of an individual cell resulted in immediate calcium response in the stimulated cell, followed rapidly by radial propagation of the signal to neighboring cells. The intercellular calcium waves were only partially reduced if apyrase was added selectively to either the mucosal or serosal bathing solution but were abolished by the bilateral apyrase addition. Calcium wave propagation was substantially reduced by disruption of the P2Y₂ gene and was further reduced in the presence of P2Y₁ receptor antagonists, indicating potential roles for adenine nucleotides in signaling. Release of UTP in response to a mechanical stimulation was demonstrated in studies in which calcium waves in P2Y₂–/– cells were restored by reconstituting P2Y₂–/– cells with the recombinant human P2Y₄ receptor. The reconstituted responses to mechanical stimulation were abolished by addition of apyrase or pretreatment with UTP to desensitize the human P2Y₄ receptor (8). These results are consistent with the notion that unilateral mechanical stimulation of a single cell results in the bilateral release of adenine and uridine nucleotides, which stimulate P2Y receptors of neighboring cells to generate calcium waves.

Levels of UTP and ATP measured in the bulk medium after mechanical stimulation of cells were considerably below the levels predicted from the robust calcium responses observed in mechanically stimulated cells (11). One explanation for this apparent contradiction is that levels of UTP in the bulk medium might reflect only a fraction of the nucleotide that accumulates transiently on release in the vicinity of the P2Y receptor. A recent report with human platelets indicates that this hypothesis is tenable, at least for ATP. Using a fusion system to anchor the ATP-specific enzyme luciferase to the outer cell surface, Beigi and colleagues (2) developed an "in situ" assay for ATP in which the cell-attached luciferase acts as a bioluminescent sensor for ATP. With this approach, these investigators demonstrated that the level of ATP in the bulk medium of thrombin-stimulated platelets was underestimated by at least one order of magnitude of the ATP concentration in the liquid layer immediately adjacent to the cell surface.

	Physiological role of nucleotide release

Top Introduction Receptors for uridine... Measurement of UTP in... Basal and stimulated release... Autocrine regulation of P2Y... Physiological role of nucleotide... Conclusions References

 
Release of nucleotides into the bloodstream may occur under various physiological and pathological conditions, e.g., exercise, tissue hypoxia, inflammation, hemolytic anemia, and endothelial injury. Highly active phosphatase activities in the blood and vasculature, however, spatially and temporally limit the actions of released nucleotides. Although UTP measurements in cell-free plasma have not been documented, the presence of uridine in micromolar concentrations in normal human plasma suggests that discrete release of UTP from circulating blood cells and/or vascular endothelial cells may be physiologically relevant.

In the airways, the P2Y₂ and the P2Y₆ receptors on the apical surface of airway epithelial cells control several of the calcium- and protein kinase C-dependent components of mucociliary clearance, e.g., ion transport, ciliary beat frequency, and mucin release. In addition, adenosine, the metabolic product of extracellular ATP, activates the A_2b receptor that constitutes a major pathway on the apical membrane regulating the cAMP-dependent chloride channel CFTR. The P2Y₂ receptor is also expressed on the basolateral cell surface along with the P2Y₁ receptor. This spatial distribution of P2Y receptors on airway epithelial cell surfaces suggests that both mucosal and serosal release of UTP and ATP nucleotides may have physiological significance.

Although ATP and UTP concentrations measured in the diluted medium bathing the mucosal surface (~200 µl/cm²) of primary cultures of resting human nasal epithelial cells were too low to activate P2 receptors (10), nucleotide levels in the thin (1 µl/cm²) film of surface liquid layer that covers the epithelial cell surface might approach threshold values for P2 receptor stimulation. Constitutive release of UTP and ATP may provide a mechanism whereby the P2Y₂ (and the P2Y₆) receptor regulates "baseline functions" in the airways, such as ciliary beat frequency, chloride secretion, and surface liquid volume. Importantly, because under normal conditions, the mucus layer and the underlying watery periciliary liquid are in continuous motion propelled by the ciliary beat cycle (~40 µm/s), shear forces generated by the airway liquid surface movement may provide a subtle mechanical stimulus for additional nucleotide release. Moreover, during some pathophysiological conditions in which the laminal periciliary liquid flow is disrupted by a mechanical stimulus (e.g., during inhalation of foreign particles) or by increased shear due to increased rates of airflow (e.g., cough), bilateral release of UTP and ATP likely occurs in amounts sufficient to promote autocrine stimulation of P2Y receptors as well as paracrine activation of nonepithelial P2Y and P2X receptors [e.g., submucosal fibroblasts and smooth muscle and inflammatory cells (Fig. 3)]. Ultimately, the relative proximity between the nucleotide release pathway and P2 receptors on one hand and the efficiency and localization of the ecto-ATPase machinery on the other hand will determine whether the basal UTP/ATP release affects the activity of P2 receptors.

View larger version (55K): [in this window] [in a new window]   FIGURE 3. Basal release of UTP and ATP on the thin paracillia liquid layer (1 µl/cm2) bathing the airway lumen results in resting nucleotide concentrations that approach threshold values for P2Y receptor (-R) stimulation. Basal nucleotide release confers one mechanism of control of mucociliary clearance in resting cells. Mechanical stress at the mucosal surface by shear forces promote enhanced bilateral nucleotide release, providing transient but robust autocrine and paracrine signals.

	Conclusions

Top Introduction Receptors for uridine... Measurement of UTP in... Basal and stimulated release... Autocrine regulation of P2Y... Physiological role of nucleotide... Conclusions References

An important remaining issue is to understand the mechanism(s) involved in the release of nucleotides from intact, nonsecretory cells. The availability of highly sensitive assays for ATP (luciferase) and UTP (UDP-glucose pyrophosphorylase) has allowed investigators to establish conditions that have identified constitutive release of nucleotides from many tissues and also improved our understanding of the role and influence of mechanical stimuli in the accumulation of extracellular UTP and ATP. This methodology should help to elucidate the pathways involved in regulated release of nucleotide from intact cells.

	References

Top Introduction Receptors for uridine... Measurement of UTP in... Basal and stimulated release... Autocrine regulation of P2Y... Physiological role of nucleotide... Conclusions References

 

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