Spatiotemporal coupling of cAMP transporter to CFTR chloride channel function in the gut epithelia.
Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel localized at apical cell membranes and exists in macromolecular complexes with a variety of signaling and transporter molecules. Here, we report that the multidrug resistance protein 4 (MRP4), a cAMP transporter, functionally and physically associates with CFTR. Adenosine-stimulated CFTR-mediated chloride currents are potentiated by MRP4 inhibition, and this potentiation is directly coupled to attenuated cAMP efflux through the apical cAMP transporter. CFTR single-channel recordings and FRET-based intracellular cAMP dynamics suggest that a compartmentalized coupling of cAMP transporter and CFTR occurs via the PDZ scaffolding protein, PDZK1, forming a macromolecular complex at apical surfaces of gut epithelia. Disrupting this complex abrogates the functional coupling of cAMP transporter activity to CFTR function. Mrp4 knockout mice are more prone to CFTR-mediated secretory diarrhea. Our findings have important implications for disorders such as inflammatory bowel disease and secretory diarrhea.
Department of Physiology, The University of Tennessee Health Science Center, 894 Union Avenue, 420 Nash, Memphis, TN 38163, USA.
Chunying
C
Li
Partha C
PC
Krishnamurthy
Himabindu
H
Penmatsa
Kevin L
KL
Marrs
Xue Qing
XQ
Wang
Manuela
M
Zaccolo
Kees
K
Jalink
Min
M
Li
Deborah J
DJ
Nelson
John D
JD
Schuetz
Anjaparavanda P
AP
Naren
D000818:Animals; D002451:Cell Compartmentation / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D018118:Chloride Channels / Q000378:metabolism; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism* / Q000502:physiology*; D003967:Diarrhea / Q000139:chemically induced; D019073:HT29 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D011485:Protein Binding; D011804:Quinolines / Q000494:pharmacology; D013997:Time Factors
D018118:Chloride Channels; D000242:Cyclic AMP; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; C073492:ABCC4 protein, human; C505032:CFTR protein, human; C059141:verlukast