Lysophosphatidic acid inhibits cholera toxin-induced secretory diarrhea through CFTR-dependent protein interactions.
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel localized primarily at the apical or luminal surfaces of epithelial cells that line the airway, gut, and exocrine glands; it is well established that CFTR plays a pivotal role in cholera toxin (CTX)-induced secretory diarrhea. Lysophosphatidic acid (LPA), a naturally occurring phospholipid present in blood and foods, has been reported to play a vital role in a variety of conditions involving gastrointestinal wound repair, apoptosis, inflammatory bowel disease, and diarrhea. Here we show, for the first time, that type 2 LPA receptors (LPA2) are expressed at the apical surface of intestinal epithelial cells, where they form a macromolecular complex with Na+/H+ exchanger regulatory factor-2 and CFTR through a PSD95/Dlg/ZO-1-based interaction. LPA inhibited CFTR-dependent iodide efflux through LPA2-mediated Gi pathway, and LPA inhibited CFTR-mediated short-circuit currents in a compartmentalized fashion. CFTR-dependent intestinal fluid secretion induced by CTX in mice was reduced substantially by LPA administration; disruption of this complex using a cell-permeant LPA2-specific peptide reversed LPA2-mediated inhibition. Thus, LPA-rich foods may represent an alternative method of treating certain forms of diarrhea.
Li
Chunying
C
Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Dandridge
Keanna S
KS
Di
Anke
A
Marrs
Kevin L
KL
Harris
Erica L
EL
Roy
Koushik
K
Jackson
John S
JS
Makarova
Natalia V
NV
Fujiwara
Yuko
Y
Farrar
Patricia L
PL
Nelson
Deborah J
DJ
Tigyi
Gabor J
GJ
Naren
Anjaparavanda P
AP
D000704:Analysis of Variance; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002772:Cholera Toxin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy*; D000076122:Disks Large Homolog 4 Protein; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers; D062826:Zonula Occludens-1 Protein
D003598:Cytoskeletal Proteins; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D008565:Membrane Proteins; D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; C093376:sodium-hydrogen exchanger regulatory factor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002772:Cholera Toxin; D000242:Cyclic AMP; C032881:lysophosphatidic acid