Latrophilin receptors: novel bronchodilator targets in asthma.
Asthma affects 300 million people worldwide. In asthma, the major cause of morbidity and mortality is acute airway narrowing, due to airway smooth muscle (ASM) hypercontraction, associated with airway remodelling. However, little is known about the transcriptional differences between healthy and asthmatic ASM cells.



To investigate the transcriptional differences between asthmatic and healthy airway smooth muscle cells (ASMC) in culture and investigate the identified targets using in vitro and ex vivo techniques.



Human asthmatic and healthy ASMC grown in culture were run on Affymetrix_Hugene_1.0_ST microarrays. Identified candidates were confirmed by PCR, and immunohistochemistry. Functional analysis was conducted using in vitro ASMC proliferation, attachment and contraction assays and ex vivo contraction of mouse airways.



We suggest a novel role for latrophilin (LPHN) receptors, finding increased expression on ASMC from asthmatics, compared with non-asthmatics in vivo and in vitro, suggesting a role in mediating airway function. A single nucleotide polymorphism in LPHN1 was associated with asthma and with increased LPHN1 expression in lung tissue. When activated, LPHNs regulated ASMC adhesion and proliferation in vitro, and promoted contraction of mouse airways and ASMC.



Given the need for novel inhibitors of airway remodelling and bronchodilators in asthma, the LPHN family may represent promising novel targets for future dual therapeutic intervention.
Woolcock Institute of Medical Research, The University of Sydney, Glebe, New South Wales, Australia.|University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, The Netherlands.
A
A
Faiz
Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.|Department of Pharmacology and Therapeutics, Lung Health Research Centre, University of Melbourne, Melbourne, Victoria, Australia.
C
C
Donovan
University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, The Netherlands.
M Ae
MA
Nieuwenhuis
University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, The Netherlands.
M
M
van den Berge
University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, The Netherlands.
D S
DS
Postma
Center for Vascular Biology Research, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
S
S
Yao
Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
C Y
CY
Park
Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
R
R
Hirsch
Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
J J
JJ
Fredberg
Woolcock Institute of Medical Research, The University of Sydney, Glebe, New South Wales, Australia.
G
G
Tjin
Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
A J
AJ
Halayko
Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
K L
KL
Rempel
Kings College London, London, UK.
J P T
JP
Ward
Kings College London, London, UK.
T
T
Lee
Department of Molecular Medicine, Institut universitaire de cardiologie et de pneumologie de Québec, Laval University, Québec, Quebec, Canada.
Y
Y
Bossé
Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, Massachusetts, USA.
D C
DC
Nickle
Centre for Heart Lung Innovation, University of British Columbia, St. Paul's Hospital, Vancouver, British Columbia, Canada.
M
M
Obeidat
University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.
Judith M
JM
Vonk
Woolcock Institute of Medical Research, The University of Sydney, Glebe, New South Wales, Australia.|Discipline of Pharmacology, Faculty of Medicine, The University of Sydney, Sydney, New South Wales, Australia.
J L
JL
Black
Woolcock Institute of Medical Research, The University of Sydney, Glebe, New South Wales, Australia.|School of Medical and Molecular Biosciences, University of Technology, Sydney, New South Wales, Australia.
B G
BG
Oliver
Center for Vascular Biology Research, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
R
R
Krishnan
Discipline of Pharmacology, Faculty of Medicine, The University of Sydney, Sydney, New South Wales, Australia.
B
B
McParland
Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.|Department of Pharmacology and Therapeutics, Lung Health Research Centre, University of Melbourne, Melbourne, Victoria, Australia.
J E
JE
Bourke
Woolcock Institute of Medical Research, The University of Sydney, Glebe, New South Wales, Australia.|Discipline of Pharmacology, Faculty of Medicine, The University of Sydney, Sydney, New South Wales, Australia.|University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands.
J K
JK
Burgess
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics* / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology; D013111:Spider Venoms / Q000494:pharmacology; D014158:Transcription, Genetic
D000109:Acetylcholine; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D013111:Spider Venoms; C467733:ADGRL1 protein, human; C513284:ADGRL3 protein, human; C530747:Adgrl1 protein, mouse; C404492:FLRT3 protein, human; C000592543:Adgrl3 protein, mouse; C020763:alpha-latrotoxin
Asthma; Asthma Genetics