title: Control of ion transport in mammalian airways by protease activated receptors type 2 (PAR-2).
abstract: Protease-activated receptors (PARs) are widely distributed in human airways. They couple to G- proteins and are activated after proteolytic cleavage of the N terminus of the receptor. Evidence is growing that PAR subtype 2 plays a pivotal role in inflammatory airway diseases, such as allergic asthma or bronchitis. However, nothing is known about the effects of PAR-2 on electrolyte transport in the native airways. PAR-2 is expressed in airway epithelial cells, where they are activated by mast cell tryptase, neutrophil proteinase 3, or trypsin. Recent studies produced conflicting results about the functional consequence of PAR-2 stimulation. Here we report that stimulation of PAR-2 receptors in mouse and human airways leads to a change in electrolyte transport and a shift from absorption to secretion. Although PAR-2 appears 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.
authors.affiliation: Institut für Physiologie, Universität Regensburg, Regensburg, Germany. uqkkunze@mailbox.uq.edu.au
authors.forename: Karl
authors.initials: K
authors.lastname: Kunzelmann
authors.forename: Jane
authors.initials: J
authors.lastname: Sun
authors.forename: Daniel
authors.initials: D
authors.lastname: Markovich
authors.forename: Jens
authors.initials: J
authors.lastname: König
authors.forename: Bettina
authors.initials: B
authors.lastname: Mürle
authors.forename: Marcus
authors.initials: M
authors.lastname: Mall
authors.forename: Rainer
authors.initials: R
authors.lastname: Schreiber
mesh_terms: D000042:Absorption; D000293:Adolescent; D000328:Adult; D000818:Animals; D001980:Bronchi; D002118:Calcium / Q000032:analysis / Q000502:physiology; D002460:Cell Line; D002648:Child; D018118:Chloride Channels / Q000502:physiology; D002712:Chlorides / Q000378:metabolism; D003106:Colon / Q000737:chemistry; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004573:Electrolytes / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D017136:Ion Transport / Q000502:physiology*; D051379:Mice; D009297:Nasal Mucosa / Q000737:chemistry / Q000502:physiology; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000032:analysis; D044464:Receptor, PAR-2 / Q000235:genetics / Q000502:physiology*; D012137:Respiratory System / Q000737:chemistry / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D014132:Trachea / Q000737:chemistry / Q000502:physiology; D014357:Trypsin / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D018118:Chloride Channels; D002712:Chlorides; D004573:Electrolytes; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012964:Sodium; D010738:Type C Phospholipases; D014357:Trypsin; D002118:Calcium