Activation of VPAC1 receptors by VIP and PACAP‐27 in human bronchial epithelial cells induces CFTR‐dependent chloride secretion

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Abstract
In the human airway epithelium, VIP/PACAP receptors are distributed in nerve fibers and in epithelial cells but their role in transepithelial ion transport have not been reported. Here, we show that human bronchial epithelial Calu‐3 cells expressed the VPAC1 receptor subtype which shares similar high affinity for VIP and PACAP‐27. The stoichiometric binding parameters characterizing the 125I‐VIP and 125I‐PACAP‐27 binding to these receptors were determined. We found that VIP (EC50∼7.6 nM) and PACAP‐27 (EC50∼10 nM) stimulated glibenclamide‐sensitive and DIDS‐insensitive iodide efflux in Calu‐3 cells. The protein kinase A (PKA) inhibitor, H‐89 and the protein kinase C (PKC) inhibitor, chelerythrine chloride prevented activation by both peptides demonstrating that PKA and PKC are part of the signaling pathway. This profile corresponds to the pharmacological signature of CFTR. In the cystic fibrosis airway epithelial IB3‐1 cell lacking functional CFTR but expressing VPAC1 receptors, neither VIP, PACAP‐27 nor forskolin stimulated chloride transport. Ussing chamber experiments demonstrated stimulation of CFTR‐dependent short‐circuit currents by VIP or PACAP‐27 applied to the basolateral but not to the apical side of Calu‐3 cells monolayers. This study shows the stimulation in human bronchial epithelial cells of CFTR‐dependent chloride secretion following activation by VIP and PACAP‐27 of basolateral VPAC1 receptors. British Journal of Pharmacology (2004) 141, 698–708. doi:10.1038/sj.bjp.0705597

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