Differential Regulations between Adenosine Triphosphate (ATP)– and Uridine Triphosphate–Induced Cl⁻Secretion in Bovine Tracheal Epithelium

Abstract

Adenosine 5'-triphosphate (ATP) stimulates airway epithelial Cl(-) secretion in a complicated manner. We examined the difference between ATP- and uridine 5'-triphosphate (UTP)-induced responses of short-circuit current (Isc) in bovine tracheal epithelium treated with amiloride. Each nucleotide caused an increase in Isc composed of the first and second peaks, where the second peak induced by ATP was higher compared with UTP. The ATP-induced second peak was inhibited by the protein kinase (PK) A inhibitor H89, saturation of P1 receptor with adenosine, and the P1 receptor antagonist 8-p-sulfophenyltheophylline, but not by the Ca(2+) chelator ethyleneglycol-bis-(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid plus the endoplasmic reticulum Ca(2+)-pump inhibitor thapsigargin, the adenosine breakdown enzyme adenosine deaminase, the ectonucleotidase inhibitor alpha,beta-methyleneadenosine 5'-diphosphate, or saturation of P2Y2 receptor with UTP. Thus, the response is associated with PKA-dependent pathway via P1-like receptor but not with Ca(2+)-dependent pathway via P2Y2 receptor, and ATP degradation products do not contribute to this response. Further, stimulation of cells with ATP increased PKA activity. In addition, pretreatment with glybenclamide, an inhibitor of cystic fibrosis transmembrane conductance regulator, reduced the second peak of Isc induced by ATP but was without effect on that induced by UTP. Therefore, ATP stimulates glybenclamide-sensitive Cl(-) secretion, and this action is partly mediated by PKA-dependent pathway via P1-like receptor.

Infection by Toxoplasma gondii , a severe parasite in neonates and AIDS patients, causes impaired anion secretion in airway epithelia

“…Extracellular ATP is considered a key signaling molecule to maintain the normal homeostasis of these processes in airway epithelia (40,41). Our studies in mouse trachea epithelia show that the response of the ATP-stimulated Cl − secretion consisted of an initial spike and a long-term component, which is consistent with previous studies in various organs (23)(24)(25). P2Y2-R is a Gq-coupled protein that is activated by extracellular ATP to promote Gq-dependent activation of PLC, which in turn regulates calcium flux and protein kinase C (PKC) activity, by an IP3 and diacylglycerol (DAG)-dependent mechanism, in Schwann cells and eye suprachoroid (42,43).…”

“…Previous studies on extracellular ATP-induced transepithelial Cl − transport in different epithelial cells have shown that the time course for the ATP response is biphasic. Different regulatory pathways are involved in mediating the ATP-induced short-circuit current (I sc ), such as the cAMP-dependent and the traditional P2-purinoceptor-linked Ca 2+ -dependent or P1-like receptordependent pathways, which activate different Cl − channels (23)(24)(25). In this study, we investigate the I sc response to extracellular ATP at 10 μM in mice trachea epithelia.…”

Purinergic P2Y₆ Receptors Induce Ca²⁺ and CFTR Dependent Cl^- Secretion in Mouse Trachea

“…Major functions comprise upregulation of Cl -and mucin secretion and ciliary motility [36][37][38]. The dominant purinergic receptors in airways are P2Y 2 receptors, which are activated by extracellular ATP or UTP [14].…”

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

“…Nevertheless, the large circulating volume in the mucosal chamber makes it unlikely that a sufficiently high concentration of adenosine could be achieved (unless the ciliated cell surface served to delay the diffusion of degradation products). Observations of direct interaction of ATP with P1 receptors exist [20], but conflicting results have been reported [35].…”