Protease-activated receptors (PARs) are widely distributed in human airways. They couple to G- proteins and are activated after proteolytic cleavage of the receptor's amino terminus. Evidence is growing that PAR subtype 2 plays a pivotal role in inflammatory airway diseases, such as allergic asthma or bronchitis. We report that stimulation of PAR-2 receptors in mouse and human airways lead to a change in electrolyte transport and a shift from absorption towards secretion. Although PAR-2 appear to be expressed on both sides of the epithelium, only basolateral stimulation results in inhibition of amiloride sensitive Na+ conductance and stimulation of both luminal Cl- channels and basolateral K+ channels. The present data indicate that these changes occur through activation of phospholipase C and increase in intracellular Ca2+, which activates basolateral SK4 K+ channels and luminal Ca2+ dependent Cl- channels. In addition, the present data suggest a PAR-2 mediated release of prostaglandin E2, which may contribute to the secretory response. In conclusion, these results provide further evidence for a role of PAR-2 in inflammatory airway disease: Stimulation of these receptors may cause accumulation of airway surface liquid which, however, may help to flush noxious stimuli away from the affected airways. Supported by Else Kröner-Fresenius-Stiftung