You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic. For video creation, please contact our Academic Video Service.
Version Summary Created by Modification Content Size Created at Operation
1
Caroline Sunggip
 -- 2670 2023-03-07 05:15:23 |
2 format correct
Conner Chen
 + 6 word(s) 2676 2023-03-08 03:07:43 |

Video Upload Options

We provide professional Academic Video Service to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Sudi, S.; Thomas, F.M.; Daud, S.K.; Ag Daud, D.M.; Sunggip, C. Extracellular Adenosine Triphosphate Sources and Signalling. Encyclopedia. Available online: https://encyclopedia.pub/entry/41919 (accessed on 19 July 2025).
Sudi S, Thomas FM, Daud SK, Ag Daud DM, Sunggip C. Extracellular Adenosine Triphosphate Sources and Signalling. Encyclopedia. Available at: https://encyclopedia.pub/entry/41919. Accessed July 19, 2025.
Sudi, Suhaini, Fiona Macniesia Thomas, Siti Kadzirah Daud, Dayang Maryama Ag Daud, Caroline Sunggip. "Extracellular Adenosine Triphosphate Sources and Signalling" Encyclopedia, https://encyclopedia.pub/entry/41919 (accessed July 19, 2025).
Sudi, S., Thomas, F.M., Daud, S.K., Ag Daud, D.M., & Sunggip, C. (2023, March 07). Extracellular Adenosine Triphosphate Sources and Signalling. In Encyclopedia. https://encyclopedia.pub/entry/41919
Sudi, Suhaini, et al. "Extracellular Adenosine Triphosphate Sources and Signalling." Encyclopedia. Web. 07 March, 2023.
Extracellular Adenosine Triphosphate Sources and Signalling
Edit
This entry is adapted from the peer-reviewed paper 10.3390/molecules28052102

Myocardial remodelling is a molecular, cellular, and interstitial adaptation of the heart in response to altered environmental demands. The heart undergoes reversible physiological remodelling in response to changes in mechanical loading or irreversible pathological remodelling induced by neurohumoral factors and chronic stress, leading to heart failure. Adenosine triphosphate (ATP) is one of the potent mediators in cardiovascular signalling that act on the ligand-gated (P2X) and G-protein-coupled (P2Y) purinoceptors via the autocrine or paracrine manners. These activations mediate numerous intracellular communications by modulating the production of other messengers, including calcium, growth factors, cytokines, and nitric oxide. ATP is known to play a pleiotropic role in cardiovascular pathophysiology, making it a reliable biomarker for cardiac protection.

extracellular ATP purinergic receptor purinergic signalling

1. Extracellular ATP Sources and Signalling

The cardiovascular system is composed of cardiomyocytes and non-myocytes, including fibroblasts, vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and circulating red blood cells (RBCs). Each of these cells communicates uniquely by releasing an autocrine/paracrine messenger known as adenosine triphosphate (ATP) in response to different stimuli. Generally, in the cardiovascular system, ATP is released via the exocytotic mechanism and/or conductive channels. ATP-containing vesicles can be released by exocytosis through vesicular nucleotide transporter (VNUT) or lysosomal vesicles [1]. The exocytosis of these cytosolic vesicles is regulated by intracellular calcium (Ca2+) levels [2]. On the other hand, the conductive release of ATP is through ion channels, including the connexin hemichannels-formed gap junction, pannexin, volume-regulated anion channels, maxi-anion channels, ATP-binding cassette (ABC) transporter, and cystic fibrosis transmembrane conductance regulator (CFTR) [3]. The mechanism of ATP release from these channels depends on various effectors, such as the opening of connexin hemichannels, and is regulated by intracellular Ca2+, reactive oxygen species (ROS), and nitric oxide (NO) levels. In contrast, pannexin can be activated by mechanical stress and P2X7 (ligand-gated (P2X)) receptor activation.
Locally released ATP may act directly on the purinergic type 2 (P2) receptors expressed abundantly in fetal and adult human hearts to influence cardiac contractility [4]. Stimulation of ATP exerts inotropic and metabotropic effects via the stimulation of the P2X and G-protein-coupled (P2Y) receptors, respectively [5]. The ATP-sensitive P2X receptor family contains seven isoforms (P2X1-7) known as extracellular ATP-gated cation channels, whose activation regulates increased intracellular Ca2+ levels and contractility in rat hearts [6]. On the other hand, the P2Y receptor family contains eight isoforms (P2Y1, 2, 4, 6, 11–14) which are G-protein-coupled receptors (GPCRs) that form a specific isoform with either Gq, Gs, or Gi [7]. In the context of ATP-activated purinergic receptors on myocytes and non-myocytes in the cardiovascular system, some of these receptor-coupled G proteins share the same intracellular signalling cascade that is greatly involved in the physiological and pathological responses.

2. Cardiomyocytes

Extracellular ATP act as a co-transmitter in vagal cardiovascular reflexes. Mechanical stimulation promotes the opening of pannexin and connexin hemichannels to release ATP from the cardiomyocytes [8][9]. Gap junction channels composed of connexin provide a means of communication between adjacent cardiomyocytes for contraction coordination [10]. Among the connexin isoforms, the connexin-43 hemichannel is predominantly distributed in the heart, being the most prominent in the ventricles [11]. Under physiological conditions, the connexin-43 hemichannel localized in the sarcolemma of cardiomyocytes and remained closed. The gating of hemichannels is positively regulated by mitogen-activated protein kinase (MAPK) [12], protein kinase A (PKA) [13], and protein kinase C (PKC) [14], and protein phosphatase indirectly blunted the opening via dephosphorylation of the connexin-43 single channel [15]. Unlike connexin-43, the pannexin-1 channel does not involve gap junction formation but instead forms a protective functional pannexin-1/P2X7 complex, mediating the release of adenosine and ATP in a brief period of ischemic/reperfusion (I/R) [16]. Additionally, pannexin 2 is predominantly involved in ATP release in atrial myocytes in response to macrophage infiltration [17]. Several conditions and mediators promote pannexin-1 channel opening, including mechanical stress [18], ATP [19], cytoplasmic Ca2+ [20], and extracellular potassium [21]. In comparison, the channel closing is regulated by the negative feedback of ATP [22] and several channel blockers, namely carbenoxolone and probenecid [23].
In cardiomyocytes, the selectivity of ATP towards P2X receptors was determined by the effective concentration (EC50) value, which shows that P2X2, P2X4, P2X5, and P2X6 exert higher ATP selectivity than P2X7, but lower as compared to P2X1 and P2X2 [24][25]. Notably, P2X4 has been identified by several studies to be highly expressed in cardiac ventricular, hence its critical role in contractile performance [25][26]. A study by Musa’s group described the variation of cardiac P2X receptor distribution in different regions of different species [27]. The group recognized P2X4 and P2X7 as highly expressed receptors in the human right atrial and sinoatrial node using quantitative polymerase chain reaction and in situ hybridization. In contrast, a high abundance of P2X5 receptors was detected in the rat hearts’ left ventricle, right atrial, and sinoatrial node [27]. The physiological significance of ATP-mediated P2X receptor activation has been highlighted in an overexpression study of the P2X4 receptor in human ventricular myocytes. The stimulation of agonists ATP and 2-methylthioadenosine-5′-o-triphosphate (2-MeSATP) on the highly expressed P2X4 receptors augments basal cardiac contractility without provoking a hypertrophic-induced heart failure [25][28][29]. This beneficial cellular response was later supported by the pharmacological treatment of MRS2339, a hydrolysis-resistant adenosine monophosphate derivative that improves the cardiac output of in vitro and in vivo working heart models [30].
On the other hand, ATP is a natural selective agonist for four subtypes of P2Y receptors, including P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11. These receptors are GPCRs that form a specific isoform with either Gq, Gs, and G12/13 alpha subunit [31][32]. The coupling of these receptors with Gq protein initiates the phospholipase C (PLC)/phosphatidylinositol-4, 5-bisphosphate (PIP2)/inositol triphosphate (IP3)-dependent Ca2+ mobilization and the activation of monomeric G proteins, Ras homolog family member A (RhoA), and Rac in cardiac muscle [33][34]. Additionally, ATP-induced P2Y11-Gs coupling yielded an increase in adenylate-cyclase-regulated cAMP production (Table 1). Interestingly, ATP-activated P2X6-G12/13 coupling in cardiomyocytes is revealed to be turned on right after the development of myocardial hypertrophy via the Gq-mediated pathway activated by the same receptor and agonist [35]. The G12/13 coupling mediates excessive production of fibrogenic factors, including transforming growth factor (TGF)-β, connective tissue growth factor (CTGF), and periostin in a Rho-dependent manner. This leads to the excessive deposition of extracellular matrix (ECM) proteins and, consequently, cardiac-fibrosis-induced heart failure.
Table 1. The underlying autocrine and paracrine signalling of extracellular ATP released from myocytes and non-myocytes in the cardiovascular system.
ATP Sources ATP-Released Channels Autocrine/Paracrine Signalling of Extracellular ATP
Cardiomyocytes Connexin-43
Pannexin 1
Pannexin 2
Pannexin-1/P2X7 complex		 P2X4 –basal cardiac contractility
P2Y/Gq—PLC—↑ Ca2+—contraction
P2Y11/Gs—cAMP—↑ Ca2+—contraction and relaxation
CF Connexin-43
Connexin-45		 P2Y2—α-SMA/TGF-β/PAI-1—sufficient scar formation and inflammatory response
VSCM Connexin-43
Pannexin-1
ABC transporters		 P2X1—basal vascular contractility
EC Cav-1
VRAC
Connexin hemichannels		 P2X4—↑ Ca2+—NO—vasodilation
P2Y/Gq—PLC—↑ Ca2+—NO—vasodilation
RBC CR-1
CTFR
Pannexin-1
VDAC		 P2Y1—↑ osmolyte permeability—absorption of sufficient nutrient
P2X1 and P2X7—PS exposure—hemolysis

3. Cardiac Fibroblasts

Cardiac fibroblasts (CFs) are a predominant non-myocyte cell type in the heart that orchestrates structural organization and corrects cardiac contraction by maintaining extracellular matrix (ECM) homeostasis. Interstitial fibrosis occurs at the earlier stage of cardiac remodelling in response to the changes in microenvironment dynamics by various stimuli [36]. At this stage, the deposition of ECM proteins, primarily collagens (type I and III), is reversible and necessary for sufficient scar formation associated with inflammatory reaction. CFs release several other pro-fibrotic activators to increase ECM synthesis, including angiotensin II (AngII), α-smooth muscle actin (α-SMA), cytokine transforming growth factor (TGF)-β, and plasminogen activator inhibitor (PAI)-1.
An early study by Braun et al. (2010) characterized high activation of purinoceptor subtypes P2Y2 by ATP and UDP stimulation, increased collagen synthesis, and the expression of α-SMA, TGF-β, and PAI-1 in CFs [37]. The same group later revealed that connexin-43 and -45 hemichannel opening contributed to the release of ATP from CFs in response to hypotonic stimulation (Table 1). This substantially activates P2Y2-mediated pro-fibrotic marker production, including α-SMA, PAI-1, and monocyte chemotactic protein-1 (MCP-1), in an extracellular signal-regulated kinase (ERK)-dependent manner [38]. The group then discovered the counterbalancing effect of ATP release in adult rat CFs. The hydrolysis of extracellular ATP released endogenously from CFs produces adenosine, which provides an anti-fibrotic response dependent on adenosine subtype 2B (A2B) receptors and activation of the cyclic adenosine monophosphate (cAMP)-PKA pathway [39]. Overexpression of A2B receptors accompanied by an increased level of cAMP is critically involved in the inhibition of CF proliferation [40][41]. Additionally, another group reported that stimulation of A2B receptors yielded a significant reduction in endothelin-1 (ET-1)-induced a-SMA expression dependent on cAMP/Epac/PI3K/Akt signalling pathways in CFs [42]. Disturbance of collagen turnover implicates the balance between synthesis and degradation of ECM proteins, leading to irreversible replacement fibrosis, as can be seen in extensive ventricular remodelling associated with heart failure.

4. Vascular Smooth Muscle Cells

Vascular smooth muscle cell (VSMC) proliferation is detrimental to vascular remodelling, growth, and the development of atherosclerotic cardiovascular disease [43]. The extracellular ATP acts as a potent stimulator for P2 receptors in the vascular smooth muscle cells (VSMCs), regulating blood vessel contraction and mitogenic effect. Pannexin-1 and connexin-43 are contributors to ATP release channels on VSMCs. Pannexin-1-released ATP regulates vasoconstriction intensity, triggered by the binding of phenylephrine on α1-adrenoreceptor [44][45]. ATP and other nucleotides are also released from the necrotic VSMCs due to the loss of membrane integrity [44][46]. In VSMCs, high ATP is released to act as a danger signal that alerts the circulating neutrophil to promote a wound-healing response. A study by Domenick’s group suggested that autocrine signalling of ATP contributed by the opening of connexin and pannexin hemichannels in response to mechanical stress in VSMCs. Treatment of non-selective hemichannel inhibitor carbenoxolone significantly attenuated the accumulation of ATP and its hydrolysis by-product inorganic pyrophosphate (PPi) [47]. Additionally, a class of integral membrane proteins known as ATP-binding cassette (ABC) transporters has been reported to play a functional role in releasing ATP [48][49]. Interestingly, these transporters are involved in regulating vascular tone in a cAMP/PKA-dependent vasorelaxation in VSMCs [50]. These findings provide a potential conduit for extracellular ATP accumulation targeting the VSMC purinergic receptors.
Uniquely, ATP possesses a dual phenotype-dependent effect on VSMCs [51][52]. ATP causes VSMCs to shift from a contractile into a proliferative phenotype in a concentration-dependent manner. A low concentration of ATP stimulates serum response factor (SRF), which enhances the expression of contractile specific proteins, smooth muscle 22 (SM22), and α-smooth muscle actin (αSMA). On the contrary, higher extracellular ATP concentration inhibits SRF activity and the specific contractile proteins, leading to the conversion of VSMCs into a synthetic phenotype [53]. Moreover, this phenotype shift is accompanied by the downregulation of the P2X1 receptor and the upregulation of mitogenic P2Y1, P2Y2, and P2Y6 receptors [54][55][56][57]. Continual release of ATP in response to high shear stress rapidly desensitized the P2X1 receptor, blunted its expression, and substantially promoted vascular wall relaxation prior to vascular remodelling via activation of mitogenic Gq-protein-coupled P2Y receptors [58][59] (Table 1). Hogarth et al. later proposed the downstream mechanism where ATP-induced P2Y receptors provoke a transient activation of the cAMP-PKA pathway, yielding an inhibitory effect on SRF activity [60].

5. Vascular Endothelial Cells

The inner cellular lining of arteries, veins, and capillaries comprises a monolayer of endothelial cells (ECs). The vascular endothelium directly interacts with the circulating blood and is considered a barrier between the blood and the vessel wall. In such an arrangement, ECs are exposed to the mechanical force generated by flowing blood (shear stress), which can exert significant autocrine, paracrine, and endocrine actions influencing VSMCs, platelets, peripheral leucocytes, and circulating RBCs [61]. The dynamic role of ECs in the vascular system is depicted by the involvement in the synthesis of vasodilator factors (NO and prostacyclin) [62][63], vasoconstricting factors (angiotensin-converting enzyme (ACE), endothelin (ET), and free radicals) [64], inflammatory mediators (interleukins (ILs) and major histocompatibility complex (MHC)) [65], and growth factors (insulin-like growth factor (IGF) and transforming growth factor (TGF)) [66]. In addition to these mediators, EC-released ATP under shear stress is mediated by the influx of extracellular Ca2+ via P2X4 receptors [67][68].
Purinergic receptors are widely distributed in the vascular system, and endothelial cells express multiple receptor subtypes, indicating their physiological and pathophysiological importance. There are several mechanisms involving ATP release channels in ECs, including caveolin-1 (Cav-1) [69], volume-regulated anion channels (VRAC) [70], and connexin hemichannels [71]. Interestingly, shear stress evoked an increase in intracellular Ca2+ where the release of ATP is localized. Yamamoto’s group revealed that the ATP release from ECs always preceded the Ca2+ increase [69]. This is supported by the action of ATP-activated purinergic receptors, which contribute to elevated intercellular Ca2+ levels via P2X4 and P2Y1, 2, 4, 6-coupled Gq-PLC pathways [67][72][73]. In this cellular context, the cytosolic pool of Ca2+ under shear stress leads to endothelial nitric oxide synthase (eNOS)-NO-mediated vasodilation (Table 1). Although NO production depends on Ca2+ level, an additional mechanism of eNOS phosphorylation by PKA, protein kinase B (PKB), and cyclic guanosine monophosphate (cGMP)-dependent protein kinase II (cGKII) may compensate for NO production in the event of intercellular Ca2+ reduction [74][75]. Disruptions of the regulation of these channels contributed to vasoconstriction.

6. Circulating Red Blood Cells

The release of cytosolic ATP from circulating red blood cells (RBCs) is reflected in the microenvironment, such as under the hypoxic condition [76], mechanical deformation [77], shear stress [78], and upon immune adherence clearance mediated by ligation of complement receptor 1 (CR1) on RBCs [79]. Throughout the decades, the mechanism of ATP release in RBCs has been revealed via several channels. A membrane-bound nucleoside transporter of RBCs is the earliest channel reported to export ATP under hypercapnic conditions [80]. Subsequent studies by Sprague’s group revealed the involvement of cystic fibrosis transmembrane conductance regulator (CFTR)-dependent adenylyl cyclase-cAMP pathway [81][82]. The same group further demonstrated that activation of CFTR and pannexin-1 hemichannel contributed to ATP release [83][84], which was supported by other works following RBCs’ deformation [85][86]. Independently, activation of the cAMP-PKA pathway promotes oligomerization of voltage-dependent anion channel (VDAC) with the translocase protein TSPO2 and nucleotide transporter that transiently accumulate extracellular ATP up to 1-2 µM within a few minutes [87].
Like other cells in the cardiovascular system, purinergic receptors, particularly P2 receptors involved in ATP-mediated signalling, are abundantly distributed in the RBCs [88]. Quantitative PCR of human RBCs by Wang et al. revealed the expression level of P2 receptors in ascending order as follows: P2Y1/P2Y4/P2Y6/P2Y11/P2Y12 < P2X1/P2X4, P2X7/P2Y2 < P2Y13 [89]. From a teleological perspective, the non-physiological release of ATP may contribute to adaptive or maladaptive responses. For instance, bacterial toxin mediates autocrine signalling of ATP to act on P2X1 and P2X7, promoting phosphatidylserine (PS) exposure on RBCs that leads to cell shrinkage [90]. Furthermore, activation of the complement system in the innate immune response exacerbates the ATP-P2X-mediated hemolysis, for which the downstream mechanism remains to be elucidated [91]. Regardless, the ramification of ATP roles on P2X activation poses a high risk of blood-related diseases, including anemia, leukemia, or autoimmunity. On the other hand, the functional role of ATP on purinergic signalling has been revealed by several studies on P2Y receptors. Several studies demonstrated the involvement of P2Y1 receptors in malarial parasite development. Autocrine activation of P2Y1 by ATP induces an osmolyte permeability pathway in human and murine RBCs, providing sufficient nutrients for the erythrocytic cycle of the parasites [92][93] (Table 1).
Interestingly, higher expression of P2Y13 in human RBCs was revealed to negatively regulate ATP release from these cells. Wang and group depicted that the metabolism of ATP to ADP, which act on P2Y13 receptors, impairs the release of ATP via the inhibition of cAMP [89]. As mentioned earlier, this inhibition may blunt the opening of CFTR and VDAC, which are cAMP-dependent ATP release channels. Moreover, paracrine signalling of ATP release from RBCs stimulates the P2 receptor on the vascular endothelium, which can promote endothelium-dependent and smooth-muscle-dependent vasodilation via the generation of vasodilators and anti-inflammatory factors such as nitric oxide (NO) and prostacyclin (PGI2) [94]. Additionally, NO also inhibits hypoxia-induced ATP release from RBCs [95].

References

  1. Taruno, A. ATP Release Channels. Int. J. Mol. Sci. 2018, 19, 808.
  2. Lazarowski, E.R. Vesicular and Conductive Mechanisms of Nucleotide Release. Purinergic Signal. 2012, 8, 359–373.
  3. Lazarowski, E.R.; Sesma, J.I.; Seminario-Vidal, L.; Kreda, S.M. Molecular Mechanisms of Purine and Pyrimidine Nucleotide Release. Adv. Pharmacol. 2011, 61, 221–261.
  4. Erlinge, D.; Burnstock, G. P2 Receptors in Cardiovascular Regulation and Disease. Purinergic Signal. 2008, 4, 1–20.
  5. Myeong, J.; Ko, J.; Kwak, M.; Kim, J.; Woo, J.; Ha, K.; Hong, C.; Yang, D.; Kim, H.J.; Jeon, J.-H.; et al. Dual Action of the Galphaq-PLCbeta-PI(4,5)P2 Pathway on TRPC1/4 and TRPC1/5 Heterotetramers. Sci. Rep. 2018, 8, 12117.
  6. Ralevic, V. P2X Receptors in the Cardiovascular System and Their Potential as Therapeutic Targets in Disease. Curr. Med. Chem. 2015, 22, 851–865.
  7. Burnstock, G. Purinergic Signaling in the Cardiovascular System. Circ. Res. 2017, 120, 207–228.
  8. Shestopalov, V.I.; Panchin, Y. Pannexins and Gap Junction Protein Diversity. Cell. Mol. Life Sci. 2008, 65, 376–394.
  9. Smyth, J.W.; Shaw, R.M. Visualizing Cardiac Ion Channel Trafficking Pathways. Methods Enzymol. 2012, 505, 187–202.
  10. Delmar, M.; Makita, N. Cardiac Connexins, Mutations and Arrhythmias. Curr. Opin. Cardiol. 2012, 27, 236–241.
  11. Liu, S.; Lan, Y.; Zhao, Y.; Zhang, Q.; Lin, T.; Lin, K.; Guo, J.; Yan, Y. Expression of Connexin 43 Protein in Cardiomyocytes of Heart Failure Mouse Model. Front. Cardiovasc. Med. 2022, 9, 1028558.
  12. Warn-Cramer, B.J.; Cottrell, G.T.; Burt, J.M.; Lau, A.F. Regulation of Connexin-43 Gap Junctional Intercellular Communication by Mitogen-Activated Protein Kinase. J. Biol. Chem. 1998, 273, 9188–9196.
  13. Lau, A.F.; Hatch-Pigott, V.; Crow, D.S. Evidence That Heart Connexin43 Is a Phosphoprotein. J. Mol. Cell. Cardiol. 1991, 23, 659–663.
  14. Bowling, N.; Huang, X.; Sandusky, G.E.; Fouts, R.L.; Mintze, K.; Esterman, M.; Allen, P.D.; Maddi, R.; McCall, E.; Vlahos, C.J. Protein Kinase C-Alpha and -Epsilon Modulate Connexin-43 Phosphorylation in Human Heart. J. Mol. Cell. Cardiol. 2001, 33, 789–798.
  15. Keyse, S.M. Protein Phosphatases and the Regulation of Mitogen-Activated Protein Kinase Signalling. Curr. Opin. Cell Biol. 2000, 12, 186–192.
  16. Vessey, D.A.; Li, L.; Kelley, M. Pannexin-I/P2X 7 Purinergic Receptor Channels Mediate the Release of Cardioprotectants Induced by Ischemic Pre- and Postconditioning. J. Cardiovasc. Pharmacol. Ther. 2010, 15, 190–195.
  17. Oishi, S.; Sasano, T.; Tateishi, Y.; Tamura, N.; Isobe, M.; Furukawa, T. Stretch of Atrial Myocytes Stimulates Recruitment of Macrophages via ATP Released through Gap-Junction Channels. J. Pharmacol. Sci. 2012, 120, 296–304.
  18. Wang, J.; Dahl, G. Pannexin1: A Multifunction and Multiconductance and/or Permeability Membrane Channel. Am. J. Physiol. Cell Physiol. 2018, 315, C290–C299.
  19. Bao, L.; Locovei, S.; Dahl, G. Pannexin Membrane Channels Are Mechanosensitive Conduits for ATP. FEBS Lett. 2004, 572, 65–68.
  20. Locovei, S.; Wang, J.; Dahl, G. Activation of Pannexin 1 Channels by ATP through P2Y Receptors and by Cytoplasmic Calcium. FEBS Lett. 2006, 580, 239–244.
  21. Silverman, W.R.; de Rivero Vaccari, J.P.; Locovei, S.; Qiu, F.; Carlsson, S.K.; Scemes, E.; Keane, R.W.; Dahl, G. The Pannexin 1 Channel Activates the Inflammasome in Neurons and Astrocytes. J. Biol. Chem. 2009, 284, 18143–18151.
  22. Qiu, F.; Dahl, G. A Permeant Regulating Its Permeation Pore: Inhibition of Pannexin 1 Channels by ATP. Am. J. Physiol. Cell Physiol. 2009, 296, C250–C255.
  23. Silverman, W.; Locovei, S.; Dahl, G. Probenecid, a Gout Remedy, Inhibits Pannexin 1 Channels. Am. J. Physiol. Cell Physiol. 2008, 295, C761–C767.
  24. Mei, Q.; Liang, B.T. P2 Purinergic Receptor Activation Enhances Cardiac Contractility in Isolated Rat and Mouse Hearts. Am. J. Physiol. Heart Circ. Physiol. 2001, 281, H334–H341.
  25. Shen, J.-B.; Pappano, A.J.; Liang, B.T. Extracellular ATP-Stimulated Current in Wild-Type and P2X4 Receptor Transgenic Mouse Ventricular Myocytes: Implications for a Cardiac Physiologic Role of P2X4 Receptors. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2006, 20, 277–284.
  26. Shen, J.-B.; Shutt, R.; Pappano, A.; Liang, B.T. Characterization and Mechanism of P2X Receptor-Mediated Increase in Cardiac Myocyte Contractility. Am. J. Physiol. Heart Circ. Physiol. 2007, 293, H3056–H3062.
  27. Musa, H.; Tellez, J.O.; Chandler, N.J.; Greener, I.D.; Maczewski, M.; Mackiewicz, U.; Beresewicz, A.; Molenaar, P.; Boyett, M.R.; Dobrzynski, H. P2 Purinergic Receptor MRNA in Rat and Human Sinoatrial Node and Other Heart Regions. Naunyn. Schmiedebergs. Arch. Pharmacol. 2009, 379, 541–549.
  28. Hu, B.; Mei, Q.B.; Yao, X.J.; Smith, E.; Barry, W.H.; Liang, B.T. A Novel Contractile Phenotype with Cardiac Transgenic Expression of the Human P2X4 Receptor. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2001, 15, 2739–2741.
  29. Hu, B.; Senkler, C.; Yang, A.; Soto, F.; Liang, B.T. P2X4 Receptor Is a Glycosylated Cardiac Receptor Mediating a Positive Inotropic Response to ATP. J. Biol. Chem. 2002, 277, 15752–15757.
  30. Zhou, S.-Y.; Mamdani, M.; Qanud, K.; Shen, J.-B.; Pappano, A.J.; Kumar, T.S.; Jacobson, K.A.; Hintze, T.; Recchia, F.A.; Liang, B.T. Treatment of Heart Failure by a Methanocarba Derivative of Adenosine Monophosphate: Implication for a Role of Cardiac Purinergic P2X Receptors. J. Pharmacol. Exp. Ther. 2010, 333, 920–928.
  31. Abbracchio, M.P.; Burnstock, G.; Boeynaems, J.-M.; Barnard, E.A.; Boyer, J.L.; Kennedy, C.; Knight, G.E.; Fumagalli, M.; Gachet, C.; Jacobson, K.A.; et al. International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy. Pharmacol. Rev. 2006, 58, 281–341.
  32. von Kugelgen, I. Pharmacological Profiles of Cloned Mammalian P2Y-Receptor Subtypes. Pharmacol. Ther. 2006, 110, 415–432.
  33. Strobaek, D.; Olesen, S.P.; Christophersen, P.; Dissing, S. P2-Purinoceptor-Mediated Formation of Inositol Phosphates and Intracellular Ca2+ Transients in Human Coronary Artery Smooth Muscle Cells. Br. J. Pharmacol. 1996, 118, 1645–1652.
  34. Lutz, S.; Freichel-Blomquist, A.; Yang, Y.; Rümenapp, U.; Jakobs, K.H.; Schmidt, M.; Wieland, T. The Guanine Nucleotide Exchange Factor P63RhoGEF, a Specific Link between Gq/11-Coupled Receptor Signaling and RhoA. J. Biol. Chem. 2005, 280, 11134–11139.
  35. Nishida, M.; Sato, Y.; Uemura, A.; Narita, Y.; Tozaki-Saitoh, H.; Nakaya, M.; Ide, T.; Suzuki, K.; Inoue, K.; Nagao, T.; et al. P2Y6 Receptor-Galpha12/13 Signalling in Cardiomyocytes Triggers Pressure Overload-Induced Cardiac Fibrosis. EMBO J. 2008, 27, 3104–3115.
  36. Frantz, S.; Hundertmark, M.J.; Schulz-Menger, J.; Bengel, F.M.; Bauersachs, J. Left Ventricular Remodelling Post-Myocardial Infarction: Pathophysiology, Imaging, and Novel Therapies. Eur. Heart J. 2022, 43, 2549–2561.
  37. Braun, O.O.; Lu, D.; Aroonsakool, N.; Insel, P.A. Uridine Triphosphate (UTP) Induces Profibrotic Responses in Cardiac Fibroblasts by Activation of P2Y2 Receptors. J. Mol. Cell. Cardiol. 2010, 49, 362–369.
  38. Lu, D.; Soleymani, S.; Madakshire, R.; Insel, P.A. ATP Released from Cardiac Fibroblasts via Connexin Hemichannels Activates Profibrotic P2Y2 Receptors. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2012, 26, 2580–2591.
  39. Lu, D.; Insel, P.A. Hydrolysis of Extracellular ATP by Ectonucleoside Triphosphate Diphosphohydrolase (ENTPD) Establishes the Set Point for Fibrotic Activity of Cardiac Fibroblasts. J. Biol. Chem. 2013, 288, 19040–19049.
  40. Chen, Y.; Epperson, S.; Makhsudova, L.; Ito, B.; Suarez, J.; Dillmann, W.; Villarreal, F. Functional Effects of Enhancing or Silencing Adenosine A2b Receptors in Cardiac Fibroblasts. Am. J. Physiol. Heart Circ. Physiol. 2004, 287, H2478–H2486.
  41. Epperson, S.A.; Brunton, L.L.; Ramirez-Sanchez, I.; Villarreal, F. Adenosine Receptors and Second Messenger Signaling Pathways in Rat Cardiac Fibroblasts. Am. J. Physiol. Cell Physiol. 2009, 296, C1171–C1177.
  42. Phosri, S.; Arieyawong, A.; Bunrukchai, K.; Parichatikanond, W.; Nishimura, A.; Nishida, M.; Mangmool, S. Stimulation of Adenosine A2B Receptor Inhibits Endothelin-1-Induced Cardiac Fibroblast Proliferation and α-Smooth Muscle Actin Synthesis through the CAMP/Epac/PI3K/Akt-Signaling Pathway. Front. Pharmacol. 2017, 8, 1–15.
  43. Burnstock, G. Purinergic Signaling and Vascular Cell Proliferation and Death. Arterioscler. Thromb. Vasc. Biol. 2002, 22, 364–373.
  44. Lohman, A.W.; Billaud, M.; Isakson, B.E. Mechanisms of ATP Release and Signalling in the Blood Vessel Wall. Cardiovasc. Res. 2012, 95, 269–280.
  45. Billaud, M.; Lohman, A.W.; Straub, A.C.; Looft-Wilson, R.; Johnstone, S.R.; Araj, C.A.; Best, A.K.; Chekeni, F.B.; Ravichandran, K.S.; Penuela, S.; et al. Pannexin1 Regulates Alpha1-Adrenergic Receptor- Mediated Vasoconstriction. Circ. Res. 2011, 109, 80–85.
  46. Buchet, R.; Tribes, C.; Rouaix, V.; Doumèche, B.; Fiore, M.; Wu, Y.; Magne, D.; Mebarek, S. Hydrolysis of Extracellular ATP by Vascular Smooth Muscle Cells Transdifferentiated into Chondrocytes Generates Pi but Not PPi. Int. J. Mol. Sci. 2021, 22, 2948.
  47. Prosdocimo, D.A.; Douglas, D.C.; Romani, A.M.; O’Neill, W.C.; Dubyak, G.R. Autocrine ATP Release Coupled to Extracellular Pyrophosphate Accumulation in Vascular Smooth Muscle Cells. Am. J. Physiol. Physiol. 2009, 296, C828–C839.
  48. Abraham, E.H.; Prat, A.G.; Gerweck, L.; Seneveratne, T.; Arceci, R.J.; Kramer, R.; Guidotti, G.; Cantiello, H.F. The Multidrug Resistance (Mdr1) Gene Product Functions as an ATP Channel. Proc. Natl. Acad. Sci. USA 1993, 90, 312–316.
  49. Reisin, I.L.; Prat, A.G.; Abraham, E.H.; Amara, J.F.; Gregory, R.J.; Ausiello, D.A.; Cantiello, H.F. The Cystic Fibrosis Transmembrane Conductance Regulator Is a Dual ATP and Chloride Channel. J. Biol. Chem. 1994, 269, 20584–20591.
  50. Robert, R.; Norez, C.; Becq, F. Disruption of CFTR Chloride Channel Alters Mechanical Properties and CAMP-Dependent Cl- Transport of Mouse Aortic Smooth Muscle Cells. J. Physiol. 2005, 568, 483–495.
  51. Vial, C.; Evans, R.J. P2X(1) Receptor-Deficient Mice Establish the Native P2X Receptor and a P2Y6-like Receptor in Arteries. Mol. Pharmacol. 2002, 62, 1438–1445.
  52. Thyberg, J. Differentiated Properties and Proliferation of Arterial Smooth Muscle Cells in Culture. Int. Rev. Cytol. 1996, 169, 183–265.
  53. Oketani, N.; Kakei, M.; Ichinari, K.; Okamura, M.; Miyamura, A.; Nakazaki, M.; Ito, S.; Tei, C. Regulation of K(ATP) Channels by P(2Y) Purinoceptors Coupled to PIP(2) Metabolism in Guinea Pig Ventricular Cells. Am. J. Physiol. Heart Circ. Physiol. 2002, 282, H757–H765.
  54. Erlinge, D.; Hou, M.; Webb, T.E.; Barnard, E.A.; Moller, S. Phenotype Changes of the Vascular Smooth Muscle Cell Regulate P2 Receptor Expression as Measured by Quantitative RT-PCR. Biochem. Biophys. Res. Commun. 1998, 248, 864–870.
  55. Hou, M.; Moller, S.; Edvinsson, L.; Erlinge, D. Cytokines Induce Upregulation of Vascular P2Y(2) Receptors and Increased Mitogenic Responses to UTP and ATP. Arterioscler. Thromb. Vasc. Biol. 2000, 20, 2064–2069.
  56. Malmsjo, M.; Hou, M.; Harden, T.K.; Pendergast, W.; Pantev, E.; Edvinsson, L.; Erlinge, D. Characterization of Contractile P2 Receptors in Human Coronary Arteries by Use of the Stable Pyrimidines Uridine 5’-O-Thiodiphosphate and Uridine 5’-O-3-Thiotriphosphate. J. Pharmacol. Exp. Ther. 2000, 293, 755–760.
  57. Wang, L.; Karlsson, L.; Moses, S.; Hultgardh-Nilsson, A.; Andersson, M.; Borna, C.; Gudbjartsson, T.; Jern, S.; Erlinge, D. P2 Receptor Expression Profiles in Human Vascular Smooth Muscle and Endothelial Cells. J. Cardiovasc. Pharmacol. 2002, 40, 841–853.
  58. Tuttle, J.L.; Nachreiner, R.D.; Bhuller, A.S.; Condict, K.W.; Connors, B.A.; Herring, B.P.; Dalsing, M.C.; Unthank, J.L. Shear Level Influences Resistance Artery Remodeling: Wall Dimensions, Cell Density, and ENOS Expression. Am. J. Physiol. Heart Circ. Physiol. 2001, 281, H1380–H1389.
  59. Wang, L.; Andersson, M.; Karlsson, L.; Watson, M.-A.; Cousens, D.J.; Jern, S.; Erlinge, D. Increased Mitogenic and Decreased Contractile P2 Receptors in Smooth Muscle Cells by Shear Stress in Human Vessels with Intact Endothelium. Arterioscler. Thromb. Vasc. Biol. 2003, 23, 1370–1376.
  60. Hogarth, D.K.; Sandbo, N.; Taurin, S.; Kolenko, V.; Miano, J.M.; Dulin, N.O. Dual Role of PKA in Phenotypic Modulation of Vascular Smooth Muscle Cells by Extracellular ATP. Am. J. Physiol. Cell Physiol. 2004, 287, C449–C456.
  61. Sandoo, A.; van Zanten, J.J.C.S.V.; Metsios, G.S.; Carroll, D.; Kitas, G.D. The Endothelium and Its Role in Regulating Vascular Tone. Open Cardiovasc. Med. J. 2010, 4, 302–312.
  62. Lamas, S.; Marsden, P.A.; Li, G.K.; Tempst, P.; Michel, T. Endothelial Nitric Oxide Synthase: Molecular Cloning and Characterization of a Distinct Constitutive Enzyme Isoform. Proc. Natl. Acad. Sci. USA 1992, 89, 6348–6352.
  63. McAdam, B.F.; Catella-Lawson, F.; Mardini, I.A.; Kapoor, S.; Lawson, J.A.; FitzGerald, G.A. Systemic Biosynthesis of Prostacyclin by Cyclooxygenase (COX)-2: The Human Pharmacology of a Selective Inhibitor of COX-2. Proc. Natl. Acad. Sci. USA 1999, 96, 272–277.
  64. Davenport, A.P.; Kuc, R.E.; Maguire, J.J.; Harland, S.P. ETA Receptors Predominate in the Human Vasculature and Mediate Constriction. J. Cardiovasc. Pharmacol. 1995, 26 (Suppl. 3), S265–S267.
  65. Mantovani, A.; Bussolino, F.; Introna, M. Cytokine Regulation of Endothelial Cell Function: From Molecular Level to the Bedside. Immunol. Today 1997, 18, 231–240.
  66. Galley, H.F.; Webster, N.R. Physiology of the Endothelium. Br. J. Anaesth. 2004, 93, 105–113.
  67. Yamamoto, K.; Korenaga, R.; Kamiya, A.; Ando, J. Fluid Shear Stress Activates Ca(2+) Influx into Human Endothelial Cells via P2X4 Purinoceptors. Circ. Res. 2000, 87, 385–391.
  68. Yamamoto, K.; Korenaga, R.; Kamiya, A.; Qi, Z.; Sokabe, M.; Ando, J. P2X(4) Receptors Mediate ATP-Induced Calcium Influx in Human Vascular Endothelial Cells. Am. J. Physiol. Heart Circ. Physiol. 2000, 279, H285–H292.
  69. Yamamoto, K.; Furuya, K.; Nakamura, M.; Kobatake, E.; Sokabe, M.; Ando, J. Visualization of Flow-Induced ATP Release and Triggering of Ca2+ Waves at Caveolae in Vascular Endothelial Cells. J. Cell Sci. 2011, 124, 3477–3483.
  70. Hisadome, K.; Koyama, T.; Kimura, C.; Droogmans, G.; Ito, Y.; Oike, M. Volume-Regulated Anion Channels Serve as an Auto/Paracrine Nucleotide Release Pathway in Aortic Endothelial Cells. J. Gen. Physiol. 2002, 119, 511–520.
  71. Mugisho, O.O.; Green, C.R.; Kho, D.T.; Zhang, J.; Graham, E.S.; Acosta, M.L.; Rupenthal, I.D. The Inflammasome Pathway Is Amplified and Perpetuated in an Autocrine Manner through Connexin43 Hemichannel Mediated ATP Release. Biochim. Biophys. Acta Gen. Subj. 2018, 1862, 385–393.
  72. Wang, S.; Chennupati, R.; Kaur, H.; Iring, A.; Wettschureck, N.; Offermanns, S. Endothelial Cation Channel PIEZO1 Controls Blood Pressure by Mediating Flow-Induced ATP Release. J. Clin. Invest. 2016, 126, 4527–4536.
  73. Schwiebert, E.M.; Zsembery, A. Extracellular ATP as a Signaling Molecule for Epithelial Cells. Biochim. Biophys. Acta Biomembr. 2003, 1615, 7–32.
  74. Boo, Y.C.; Sorescu, G.; Boyd, N.; Shiojima, I.; Walsh, K.; Du, J.; Jo, H. Shear Stress Stimulates Phosphorylation of Endothelial Nitric-Oxide Synthase at Ser1179 by Akt-Independent Mechanisms: Role of Protein Kinase A. J. Biol. Chem. 2002, 277, 3388–3396.
  75. Bae, S.W.; Kim, H.S.; Cha, Y.N.; Park, Y.S.; Jo, S.A.; Jo, I. Rapid Increase in Endothelial Nitric Oxide Production by Bradykinin Is Mediated by Protein Kinase A Signaling Pathway. Biochem. Biophys. Res. Commun. 2003, 306, 981–987.
  76. Grygorczyk, R.; Orlov, S.N. Effects of Hypoxia on Erythrocyte Membrane Properties—Implications for Intravascular Hemolysis and Purinergic Control of Blood Flow. Front. Physiol. 2017, 8, 1110.
  77. Mancuso, J.E.; Jayaraman, A.; Ristenpart, W.D. Centrifugation-Induced Release of ATP from Red Blood Cells. PLoS ONE 2018, 13, e0203270.
  78. Wan, J.; Forsyth, A.M.; Stone, H.A. Red Blood Cell Dynamics: From Cell Deformation to ATP Release. Integr. Biol. (Camb) 2011, 3, 972–981.
  79. Melhorn, M.I.; Brodsky, A.S.; Estanislau, J.; Khoory, J.A.; Illigens, B.; Hamachi, I.; Kurishita, Y.; Fraser, A.D.; Nicholson-Weller, A.; Dolmatova, E.; et al. CR1-Mediated ATP Release by Human Red Blood Cells Promotes CR1 Clustering and Modulates the Immune Transfer Process*. J. Biol. Chem. 2013, 288, 31139–31153.
  80. Bergfeld, G.R.; Forrester, T. Release of ATP from Human Erythrocytes in Response to a Brief Period of Hypoxia and Hypercapnia. Cardiovasc. Res. 1992, 26, 40–47.
  81. Sprague, R.S.; Ellsworth, M.L.; Stephenson, A.H.; Kleinhenz, M.E.; Lonigro, A.J. Deformation-Induced ATP Release from Red Blood Cells Requires CFTR Activity. Am. J. Physiol. 1998, 275, H1726–H1732.
  82. Sprague, R.S.; Ellsworth, M.L.; Stephenson, A.H.; Lonigro, A.J. Participation of CAMP in a Signal-Transduction Pathway Relating Erythrocyte Deformation to ATP Release. Am. J. Physiol. Cell Physiol. 2001, 281, C1158–C1164.
  83. Ellsworth, M.L.; Ellis, C.G.; Sprague, R.S. Role of Erythrocyte-Released ATP in the Regulation of Microvascular Oxygen Supply in Skeletal Muscle. Acta Physiol. 2016, 216, 265–276.
  84. Sridharan, M.; Adderley, S.P.; Bowles, E.A.; Egan, T.M.; Stephenson, A.H.; Ellsworth, M.L.; Sprague, R.S. Pannexin 1 Is the Conduit for Low Oxygen Tension-Induced ATP Release from Human Erythrocytes. Am. J. Physiol. Heart Circ. Physiol. 2010, 299, H1146–H1152.
  85. Forsyth, A.M.; Wan, J.; Owrutsky, P.D.; Abkarian, M.; Stone, H.A. Multiscale Approach to Link Red Blood Cell Dynamics, Shear Viscosity, and ATP Release. Proc. Natl. Acad. Sci. USA 2011, 108, 10986–10991.
  86. Montalbetti, N.; Leal Denis, M.F.; Pignataros, O.P.; Kobatake, E.; Lazarowski, E.R.; Schwarzbaum, P.J. Homeostasis of Extracellular ATP in Human Erythrocytes. J. Biol. Chem. 2011, 286, 38397–38407.
  87. Marginedas-Freixa, I.; Alvarez, C.L.; Moras, M.; Leal Denis, M.F.; Hattab, C.; Halle, F.; Bihel, F.; Mouro-Chanteloup, I.; Lefevre, S.D.; Le Van Kim, C.; et al. Human Erythrocytes Release ATP by a Novel Pathway Involving VDAC Oligomerization Independent of Pannexin-1. Sci. Rep. 2018, 8, 11384.
  88. Skals, M.; Leipziger, J.; Praetorius, H.A. Haemolysis Induced by α-Toxin from Staphylococcus Aureus Requires P2X Receptor Activation. Pflügers Arch. Eur. J. Physiol. 2011, 462, 669.
  89. Wang, L.; Olivecrona, G.; Gotberg, M.; Olsson, M.L.; Winzell, M.S.; Erlinge, D. ADP Acting on P2Y13 Receptors Is a Negative Feedback Pathway for ATP Release from Human Red Blood Cells. Circ. Res. 2005, 96, 189–196.
  90. Fagerberg, S.K.; Skals, M.; Leipziger, J.; Praetorius, H.A. P2X Receptor-Dependent Erythrocyte Damage by α-Hemolysin from Escherichia Coli Triggers Phagocytosis by THP-1 Cells. Toxins 2013, 5, 472–487.
  91. Hejl, J.L.; Skals, M.; Leipziger, J.; Praetorius, H.A. P2X Receptor Stimulation Amplifies Complement-Induced Haemolysis. Pflügers Arch. Eur. J. Physiol. 2013, 465, 529–541.
  92. Tanneur, V.; Duranton, C.; Brand, V.B.; Sandu, C.D.; Akkaya, C.; Kasinathan, R.S.; Gachet, C.; Sluyter, R.; Barden, J.A.; Wiley, J.S.; et al. Purinoceptors Are Involved in the Induction of an Osmolyte Permeability in Malaria-Infected and Oxidized Human Erythrocytes. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2006, 20, 133–135.
  93. Kirk, K.; Lehane, A.M. Membrane Transport in the Malaria Parasite and Its Host Erythrocyte. Biochem. J. 2014, 457, 1–18.
  94. Sprague, R.S.; Ellsworth, M.L. Erythrocyte-Derived ATP and Perfusion Distribution: Role of Intracellular and Intercellular Communication. Microcirculation 2012, 19, 430–439.
  95. Olearczyk, J.J.; Ellsworth, M.L.; Stephenson, A.H.; Lonigro, A.J.; Sprague, R.S. Nitric Oxide Inhibits ATP Release from Erythrocytes. J. Pharmacol. Exp. Ther. 2004, 309, 1079–1084.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Suhaini Sudi
,
Fiona Macniesia Thomas
,
Siti Kadzirah Daud
,
Dayang Maryama Ag Daud
,
Caroline Sunggip
View Times: 530
Revisions: 2 times (View History)
Update Date: 08 Mar 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Academic Video Service
    Feedback