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.
Li
Chunying
C
Department of Physiology, The University of Tennessee Health Science Center, 894 Union Avenue, 420 Nash, Memphis, TN 38163, USA.
Krishnamurthy
Partha C
PC
Penmatsa
Himabindu
H
Marrs
Kevin L
KL
Wang
Xue Qing
XQ
Zaccolo
Manuela
M
Jalink
Kees
K
Li
Min
M
Nelson
Deborah J
DJ
Schuetz
John D
JD
Naren
Anjaparavanda P
AP
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