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Involvement of apical P2Y₂ receptor-regulated CFTR activity in muscarinic stimulation of Cl^– reabsorption in rat submandibular gland

Departments of ¹Functional Bioscience, ²Morphological Biology, and ³Physiological Science and Molecular Biology, Fukuoka Dental College, Sawara-ku, Fukuoka, Japan

Submitted 18 October 2007 ; accepted in final form 5 March 2008

Previously, we presented in vivo evidence for a physiological significance of cAMP-regulated CFTR Cl^– channels in Ca²⁺-activated Cl^– reabsorption in the ductal system of the rat submandibular gland. Here, we address the mechanism by which basal CFTR activation contributes to the transepithelial Cl^– movement evoked by muscarinic stimulation. The Cl^– concentration ([Cl^–]) was increased in the final saliva from rat submandibular gland during pilocarpine stimulation when a small interfering RNA for CFTR or a specific CFTR inhibitor, CFTR_inh-172, was injected retrogradely into the gland's own duct, indicating that basal CFTR activation is involved in Cl^– reabsorption. Systemically administered propranolol failed to alter the [Cl^–], suggesting little involvement of a β-adrenergic pathway in the Cl^– movement that occurs through basal CFTR activation. Intraductal injection of suramin (a nonspecific P2-receptor antagonist) increased the salivary [Cl^–], indicating the existence of endogenous purinergic activation. Upon separate intraductal injection, ATP and a P2Y₂-receptor agonist, UTP, decreased the salivary [Cl^–] almost equipotently. CFTR_inh-172 and suramin each prevented these effects, whereas 2',3'-O-(4-benzoylbenzoyl)-ATP (Bz-ATP), a P2X₇ agonist, had no specific effect. Pilocarpine stimulation evoked ATP secretion into the salivary fluid. Immunohistochemistry revealed the partial coexistence of CFTR and P2Y₂ receptors on the luminal surface of epithelial cells in the striated ducts of this gland. These results raise the possibility that muscarinic stimulation-induced Cl^– reabsorption occurs through basal CFTR activity and that this is regulated by P2Y₂ receptors in the ductal epithelium via stimulation by ATP secreted into the salivary fluid.

salivary; duct; reabsorption; P2Y₂ receptor; cystic fibrosis transmembrane conductance regulator

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