Novel identification of the free fatty acid receptor FFAR1 that promotes contraction in airway smooth muscle.
Obesity is one of the major risk factors for asthma. Previous studies have demonstrated that free fatty acid levels are elevated in the plasma of obese individuals. Medium- and long-chain free fatty acids act as endogenous ligands for the free fatty acid receptors FFAR1/GPR40 and FFAR4/GPR120, which couple to Gq proteins. We investigated whether FFAR1 and FFAR4 are expressed on airway smooth muscle and whether they activate Gq-coupled signaling and modulate airway smooth muscle tone. We detected the protein expression of FFAR1 and FFAR4 in freshly dissected native human and guinea pig airway smooth muscle and cultured human airway smooth muscle (HASM) cells by immunoblotting and immunohistochemistry. The long-chain free fatty acids (oleic acid and linoleic acid) and GW9508 (FFAR1/FFAR4 dual agonist) dose-dependently stimulated transient intracellular Ca(2+) concentration ([Ca(2+)]i) increases and inositol phosphate synthesis in HASM cells. Downregulation of FFAR1 or FFAR4 in HASM cells by small interfering RNA led to a significant inhibition of the long-chain free fatty acids-induced transient [Ca(2+)]i increases. Oleic acid, linoleic acid, or GW9508 stimulated stress fiber formation in HASM cells, potentiated acetylcholine-contracted guinea pig tracheal rings, and attenuated the relaxant effect of isoproterenol after an acetylcholine-induced contraction. In contrast, TUG-891 (FFAR4 agonist) did not induce the stress fiber formation or potentiate acetylcholine-induced contraction. These results suggest that FFAR1 is the functionally dominant free fatty acid receptor in both human and guinea pig airway smooth muscle. The free fatty acid sensors expressed on airway smooth muscle could be an important modulator of airway smooth muscle tone.
Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York; Department of Dento-oral Anesthesiology, Tohoku University Graduate School of Dentistry, Sendai, Japan; and mizuta@m.tohoku.ac.jp.
Kentaro
K
Mizuta
Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York;
Yi
Y
Zhang
Department of Dento-oral Anesthesiology, Tohoku University Graduate School of Dentistry, Sendai, Japan; and.
Fumiko
F
Mizuta
Department of Dento-oral Anesthesiology, Tohoku University Graduate School of Dentistry, Sendai, Japan; and.
Hiroshi
H
Hoshijima
Department of Anesthesiology, Chemotherapy Research Institute, Kaken Hospital, International University of Health and Welfare, Chiba, Japan.
Toshiya
T
Shiga
Department of Dento-oral Anesthesiology, Tohoku University Graduate School of Dentistry, Sendai, Japan; and.
Eiji
E
Masaki
Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York;
Charles W
CW
Emala
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D019787:Linoleic Acid / Q000494:pharmacology; D008744:Methylamines / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009129:Muscle Tonus / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000378:metabolism*; D019301:Oleic Acid / Q000494:pharmacology; D010666:Phenylpropionates / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D022502:Stress Fibers / Q000378:metabolism
C585065:3-(4-((4-fluoro-4'-methyl-(1,1'-biphenyl)-2-yl)methoxy)phenyl)propanoic acid; D001713:Biphenyl Compounds; C473034:FFAR1 protein, human; C515630:GW9508; D008744:Methylamines; D010666:Phenylpropionates; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; D019301:Oleic Acid; D019787:Linoleic Acid; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
FFAR1; FFAR4; Gq-coupled receptor; airway smooth muscle; free fatty acid