title: CD151, a laminin receptor showing increased expression in asthmatic patients, contributes to airway hyperresponsiveness through calcium signaling.
abstract: Airway smooth muscle (ASM) contraction underpins airway constriction; however, underlying mechanisms for airway hyperresponsiveness (AHR) remain incompletely defined. CD151, a 4-transmembrane glycoprotein that associates with laminin-binding integrins, is highly expressed in the human lung. The role of CD151 in ASM function and its relationship to asthma have yet to be elucidated.
  
  
  
  We sought to ascertain whether CD151 expression is clinically relevant to asthma and whether CD151 expression affects AHR.
  
  
  
  Using immunohistochemical analysis, we determined the expression of CD151 in human bronchial biopsy specimens from patients with varying asthma severities and studied the mechanism of action of CD151 in the regulation of ASM contraction and bronchial caliber in vitro, ex vivo, and in vivo.
  
  
  
  The number of CD151+ASM cells is significantly greater in patients with moderate asthma compared with those in healthy nonasthmatic subjects. From loss- and gain-of-function studies, we reveal that CD151 is required for and enhances G protein-coupled receptor (GPCR)-induced peak intracellular calcium release, the primary determinant of excitation-contraction coupling. We show that the localization of CD151 can also be perinuclear/cytoplasmic and offer an explanation for a novel functional role for CD151 in supporting protein kinase C (PKC) translocation to the cell membrane in GPCR-mediated ASM contraction at this site. Importantly, CD151-/-mice are refractory to airway hyperreactivity in response to allergen challenge.
  
  
  
  We identify a role for CD151 in human ASM contraction. We implicate CD151 as a determinant of AHR in vivo, likely through regulation of GPCR-induced calcium and PKC signaling. These observations have significant implications in understanding the mechanism for AHR and the efficacy of new and emerging therapeutics.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Yongkang
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: John Kit Chung
authors.initials: JKC
authors.lastname: Tam
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Sheryl S L
authors.initials: SSL
authors.lastname: Tan
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Yee Kit
authors.initials: YK
authors.lastname: Tai
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Chin Yein
authors.initials: CY
authors.lastname: Chin
authors.affiliation: Department of Pharmacology and Therapeutics, and Lung Health Research Centre, University of Melbourne, Melbourne, Australia.
authors.forename: Alastair G
authors.initials: AG
authors.lastname: Stewart
authors.affiliation: School of Biomedical Sciences, University of Newcastle, Newcastle, Australia.
authors.forename: Leonie
authors.initials: L
authors.lastname: Ashman
authors.affiliation: Institute for Protein Research, Osaka University, Osaka, Japan.
authors.forename: Kiyotoshi
authors.initials: K
authors.lastname: Sekiguchi
authors.affiliation: Department of Pharmacology and Therapeutics, and Lung Health Research Centre, University of Melbourne, Melbourne, Australia.
authors.forename: Shenna Y
authors.initials: SY
authors.lastname: Langenbach
authors.affiliation: Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada; Biology of Breathing Theme, Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada.
authors.forename: Gerald
authors.initials: G
authors.lastname: Stelmack
authors.affiliation: Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada; Biology of Breathing Theme, Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: tran_thai@nuhs.edu.sg.
authors.forename: Thai
authors.initials: T
authors.lastname: Tran
mesh_terms: D000328:Adult; D000818:Animals; D001249:Asthma / Q000378:metabolism* / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid; D020013:Calcium Signaling; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D060185:Tetraspanin 24 / Q000235:genetics / Q000378:metabolism*
chemical_list: C554715:CD151 protein, human; D060185:Tetraspanin 24; D011493:Protein Kinase C
keywords: Airway hyperresponsiveness; CD151; G protein–coupled receptor; PKC; airway smooth muscle; asthma; calcium; contraction; integrins; laminin; tetraspanin