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

• Published in: Cellular physiology and biochemistry Vol. 16; no. 1-3; pp. 99 - 108
• Main Authors: Schreiber, Rainer, Kunzelmann, Karl
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland 2005
• Subjects: Adenosine Diphosphate - pharmacology; Amiloride - pharmacology; Animals; Base Sequence; Calcium - metabolism; Chlorides - metabolism; Cyclic AMP - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; In Vitro Techniques; Ion Transport - drug effects; Mice; Original Paper; Potassium - metabolism; Purinergic P2 Receptor Agonists; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2 - genetics; Receptors, Purinergic P2 - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sodium - metabolism; Trachea - drug effects; Trachea - metabolism; Uridine Diphosphate - pharmacology; Uridine Triphosphate - analogs & derivatives; Uridine Triphosphate - pharmacology
• ISSN: 1015-8987; 1421-9778
• DOI: 10.1159/000087736

In airways Cl - secretion is activated and Na + absorption is inhibited when P2Y 2 receptors are stimulated by ATP or UTP. Both nucleotides are subject to degradation to ADP and UDP by ecto-nucleotidases. Here we show that these metabolites change electrolyte transport by stimulation of P2Y 6 receptors in mouse trachea. Immunohistochemistry confirmed luminal and basolateral expression of P2Y 6 receptors. In Ussing chamber experiments luminal ADP, UDP or the P2Y 6 receptor agonist INS48823 induced both transient and persistent increase in short circuit currents (I SC ). Activation of I SC was inhibited by the P2Y 6 receptor blocker PPADS. The transient response was inhibited by DIDS, whereas the persistent I SC was inhibited by glibenclamide and by the protein kinase A (PKA) blocker H-89. Moreover, sustained activation of I SC by luminal UDP was inhibited by blocking basolateral K + channels with 293B. Possible effects of diphosphates on P2Y 1 or adenosine receptors were excluded by the inhibitors MRS2179 and 8-SPT, respectively. Inhibition of amiloride sensitive Na + absorption was only seen after blocking basolateral K + channels with 293B. In contrast, Cl - secretion activated by basolateral ADP or UDP was only transient and was blocked by the sk4 K + channel blocker clotrimazole. In summary, activation of luminal P2Y 6 receptors in the airways shifts electrolyte transport towards secretion by increasing intracellular Ca + and activation of PKA.