Stimulation of gastric acid secretion by rabbit parietal cell A_2B adenosine receptor activation

Abstract

Adenosine modulates different functional activities in many cells of the gastrointestinal tract; some of them are believed to be mediated by interaction with its four G protein-coupled receptors. The renewed interest in the adenosine A2B receptor (A2BR) subtype can be traced by studies in which the introduction of new genetic and chemical tools has widened the pharmacological and structural knowledge of this receptor as well as its potential therapeutic use in cancer and inflammation- or hypoxia-related pathologies. In the acid-secreting parietal cells of the gastric mucosa, the use of various radioligands for adenosine receptors suggested the presence of the A2 adenosine receptor subtype(s) on the cell surface. Recently, we confirmed A2BR expression in native, nontransformed parietal cells at rest by using flow cytometry and confocal microscopy. In this study, we show that A2BR is functional in primary rabbit gastric parietal cells, as indicated by the fact that agonist binding to A2BR increased adenylate cyclase activity and acid production. In addition, both acid production and radioligand binding of adenosine analogs to isolated cell membranes were potently blocked by selective A2BR antagonists, whereas ligands for A1, A2A, and A3 adenosine receptors failed to abolish activation. We conclude that rabbit gastric parietal cells possess functional A2BR proteins that are coupled to Gs and stimulate HCl production upon activation. Whether adenosine- and A2BR-mediated functional responses play a role in human gastric pathophysiology is yet to be elucidated.

Adenosine: Direct and Indirect Actions on Gastric Acid Secretion

“…Our study demonstrated that, in rabbits, the gastric parietal cell is endowed with a density of A2B receptors sufficient to promote acid secretion even though the affinity constants were similar to those reported in other tissues and cell models (Klotz et al, 1998 ; Fredholm et al, 2001b , 2011 ). We also demonstrated that such activation was mediated by a cAMP rise and not by calcium (Arin et al, 2015b ). In human crypt epithelial cells, activation of A2B receptor by adenosine promotes Cl − secretion via intracellular cAMP increase (Antonioli et al, 2008 ).…”

“…In a bimodal response, ATP would act first on P2 receptors inducing ACh and ATP co-release (Vieira et al, 2009 ) and the enzymatically generated adenosine would induce or reduce ACh release upon binding to A2A or A1 receptor, respectively (Duarte-Araujo et al, 2009 ). The fact that gastric parietal cells and D cells express A2B (Arin et al, 2015a , b ) and A2A (Yip et al, 2004a ), respectively, suggests that adenosine is a bona fide extracellular mediator in the neighborhood; it is possible, therefore, to speculate that the autocrine regulation described above for myenteric neurons might operate too in the cholinergic fibers of the ENS innervating both parietal and D cells, representing an additional regulatory mechanism for adenosine in gastric acid secretion.…”

“…Low oxygen tension in areas of tissues with poor blood supply stimulates the formation of hypoxia-inducible factor-1. Having in mind that this transcription factor is a central regulator of oxygen homeostasis and that it has been implicated in transcriptional regulation of anti-inflammatory or tissue-protecting signaling (Hart et al, 2011 ; Eltzschig et al, 2012 ), it is tempting to speculate that increased extracellular adenosine and parietal cell A2B expression (Arin et al, 2015b ) may also be implicated in stomach protection from damage.…”

“…Using parietal cells isolated from rabbit gastric glands of the stomach corpus, we performed the pharmacological identification of A2B and demonstrated that degradation of endogenous adenosine secondary to ADA treatment reduced acid secretion (Arin et al, 2015b ). The cells we used were representative populations of primary parietal cells at rest, thus suggesting that endogenous adenosine may contribute to spontaneous acid production in basal conditions.…”

“…The cells we used were representative populations of primary parietal cells at rest, thus suggesting that endogenous adenosine may contribute to spontaneous acid production in basal conditions. Furthermore, exposure of such cells to adenosine analogs stimulated acid secretion, and further pharmacologic and functional studies revealed that A2B was the only receptor involved (Arin et al, 2015b ). Our study demonstrated that, in rabbits, the gastric parietal cell is endowed with a density of A2B receptors sufficient to promote acid secretion even though the affinity constants were similar to those reported in other tissues and cell models (Klotz et al, 1998 ; Fredholm et al, 2001b , 2011 ).…”