Effect of P2X(7) Receptor Knockout on Exocrine Secretion of Pancreas, Salivary Glands and Lacrimal Glands

Overview

Journal J Physiol

Specialty Physiology

Date 2010 Jul 21

PMID 20643770

Citations 32

Authors

Ivana Novak

Ida M Jans

Louise Wohlfahrt

Affiliations

Soon will be listed here.

Abstract

The purinergic P2X(7) receptors are expressed in different cell types where they have varied functions, including regulation of cell survival. The P2X(7) receptors are also expressed in exocrine glands, but their integrated role in secretion is unclear. The aim of our study was to determine whether the P2X(7) receptors affect fluid secretion in pancreas, salivary glands and tear glands. We monitored gland secretions in in vivo preparations of wild-type and P2X(7)(-/-) (Pfizer) mice stimulated with pilocarpine. In cell preparations from pancreas, parotid and lacrimal glands we measured ATP release and intracellular Ca(2+) activity using Fura-2. The data showed that pancreatic secretion and salivary secretions were reduced in P2X(7)(-/-) mice, and in contrast, tear secretion was increased in P2X(7)(-/-) mice. The secretory phenotype was also dependent on the sex of the animal, such that males were more dependent on the P2X(7) receptor expression. ATP release in all cell preparations could be elicited by carbachol and other agonists, and this was independent of the P2X(7) receptor expression. ATP and carbachol increased intracellular Ca(2+) activity, but responses depended on the gland type, presence of the P2X(7) receptor and the sex of the animal. Together, these results demonstrate that cholinergic stimulation leads to release of ATP that can via P2X(7) receptors up-regulate pancreatic and salivary secretion but down-regulate tear secretion. Our data also indicate that there is an interaction between purinergic and cholinergic receptor signalling and that function of the P2X(7) receptor is suppressed in females. We conclude that the P2X(7) receptors are important in short-term physiological regulation of exocrine gland secretion.

Citing Articles

Advances in cellular and molecular pathways of salivary gland damage in Sjögren's syndrome.

Qi W, Tian J, Wang G, Yan Y, Wang T, Wei Y Front Immunol. 2024; 15:1405126.

PMID: 39050857 PMC: 11266040. DOI: 10.3389/fimmu.2024.1405126.

P2X7 receptor knockout does not alter renal function or prevent angiotensin II-induced kidney injury in F344 rats.

Nespoux J, Monaghan M, Jones N, Stewart K, Denby L, Czopek A Sci Rep. 2024; 14(1):9573.

PMID: 38670993 PMC: 11053004. DOI: 10.1038/s41598-024-59635-x.

Purinergic Signaling in Oral Tissues.

Zuccarini M, Giuliani P, Ronci M, Caciagli F, Caruso V, Ciccarelli R Int J Mol Sci. 2022; 23(14).

PMID: 35887132 PMC: 9318746. DOI: 10.3390/ijms23147790.

Pathophysiological Role of Purinergic P2X Receptors in Digestive System Diseases.

An Q, Yue G, Yang X, Lou J, Shan W, Ding J Front Physiol. 2022; 12:781069.

PMID: 35002763 PMC: 8740087. DOI: 10.3389/fphys.2021.781069.

Development of a functional salivary gland tissue chip with potential for high-content drug screening.

Song Y, Uchida H, Sharipol A, Piraino L, Mereness J, Ingalls M Commun Biol. 2021; 4(1):361.

PMID: 33742114 PMC: 7979686. DOI: 10.1038/s42003-021-01876-x.

References

BARKA T . Biologically active polypeptides in submandibular glands. J Histochem Cytochem. 1980; 28(8):836-59. DOI: 10.1177/28.8.7003006. View

Henriksen K, Novak I . Effect of ATP on intracellular pH in pancreatic ducts involves P2X7 receptors. Cell Physiol Biochem. 2003; 13(2):93-102. DOI: 10.1159/000070253. View

Khakh B, Zhou X, Sydes J, Galligan J, Lester H . State-dependent cross-inhibition between transmitter-gated cation channels. Nature. 2000; 406(6794):405-10. DOI: 10.1038/35019066. View

Simeone D, Yule D, Logsdon C, Williams J . Ca2+ signaling through secretagogue and growth factor receptors on pancreatic AR42J cells. Regul Pept. 1995; 55(2):197-206. DOI: 10.1016/0167-0115(94)00107-9. View

Sorensen C, Novak I . Visualization of ATP release in pancreatic acini in response to cholinergic stimulus. Use of fluorescent probes and confocal microscopy. J Biol Chem. 2001; 276(35):32925-32. DOI: 10.1074/jbc.M103313200. View

Jayasinghe N, Cope G, Jacob S . Morphometric studies on the development and sexual dimorphism of the submandibular gland of the mouse. J Anat. 1990; 172:115-27. PMC: 1257208. View

Walcott B, Birzgalis A, Moore L, Brink P . Fluid secretion and the Na+-K+-2Cl- cotransporter in mouse exorbital lacrimal gland. Am J Physiol Cell Physiol. 2005; 289(4):C860-7. DOI: 10.1152/ajpcell.00526.2004. View

Crooke A, Guzman-Aranguez A, Peral A, Abdurrahman M, Pintor J . Nucleotides in ocular secretions: their role in ocular physiology. Pharmacol Ther. 2008; 119(1):55-73. DOI: 10.1016/j.pharmthera.2008.04.002. View

Haanes K, Novak I . ATP storage and uptake by isolated pancreatic zymogen granules. Biochem J. 2010; 429(2):303-11. DOI: 10.1042/BJ20091337. View

10.

Garcia-Marcos M, Fontanils U, Aguirre A, Pochet S, Dehaye J, Marino A . Role of sodium in mitochondrial membrane depolarization induced by P2X7 receptor activation in submandibular glands. FEBS Lett. 2005; 579(24):5407-13. DOI: 10.1016/j.febslet.2005.08.074. View

11.

Novak I . ATP as a signaling molecule: the exocrine focus. News Physiol Sci. 2003; 18:12-7. DOI: 10.1152/nips.01409.2002. View

12.

Nicke A, Kuan Y, Masin M, Rettinger J, Marquez-Klaka B, Bender O . A functional P2X7 splice variant with an alternative transmembrane domain 1 escapes gene inactivation in P2X7 knock-out mice. J Biol Chem. 2009; 284(38):25813-22. PMC: 2757983. DOI: 10.1074/jbc.M109.033134. View

13.

Pochet S, Garcia-Marcos M, Seil M, Otto A, Marino A, Dehaye J . Contribution of two ionotropic purinergic receptors to ATP responses in submandibular gland ductal cells. Cell Signal. 2007; 19(10):2155-64. DOI: 10.1016/j.cellsig.2007.06.012. View

14.

Leipziger J . Control of epithelial transport via luminal P2 receptors. Am J Physiol Renal Physiol. 2003; 284(3):F419-32. DOI: 10.1152/ajprenal.00075.2002. View

15.

Ohlendorff S, Tofteng C, Jensen J, Petersen S, Civitelli R, Fenger M . Single nucleotide polymorphisms in the P2X7 gene are associated to fracture risk and to effect of estrogen treatment. Pharmacogenet Genomics. 2007; 17(7):555-67. DOI: 10.1097/FPC.0b013e3280951625. View

16.

Hansen M, Krabbe S, Novak I . Purinergic receptors and calcium signalling in human pancreatic duct cell lines. Cell Physiol Biochem. 2008; 22(1-4):157-68. DOI: 10.1159/000149793. View

17.

Cheewatrakoolpong B, Gilchrest H, Anthes J, Greenfeder S . Identification and characterization of splice variants of the human P2X7 ATP channel. Biochem Biophys Res Commun. 2005; 332(1):17-27. DOI: 10.1016/j.bbrc.2005.04.087. View

18.

Praetorius H, Leipziger J . ATP release from non-excitable cells. Purinergic Signal. 2009; 5(4):433-46. PMC: 2776134. DOI: 10.1007/s11302-009-9146-2. View

19.

Ishibashi K, Okamura K, Yamazaki J . Involvement of apical P2Y2 receptor-regulated CFTR activity in muscarinic stimulation of Cl(-) reabsorption in rat submandibular gland. Am J Physiol Regul Integr Comp Physiol. 2008; 294(5):R1729-36. DOI: 10.1152/ajpregu.00758.2007. View

20.

Fuller S, Stokes L, Skarratt K, Gu B, Wiley J . Genetics of the P2X7 receptor and human disease. Purinergic Signal. 2009; 5(2):257-62. PMC: 2686826. DOI: 10.1007/s11302-009-9136-4. View