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Ceramide activates JNK to inhibit a cAMP‐gated K + conductance and Cl ‐ secretion in intestinal epithelia
Author(s) -
Saslowsky David E.,
Tanaka Noriyuki,
Reddy Krishna P.,
Lencer Wayne I.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-116467
Subject(s) - sphingomyelin , ceramide , secretion , sphingomyelin phosphodiesterase , microbiology and biotechnology , epithelial polarity , sphingosine , lipid signaling , chemistry , kinase , sphingolipid , biology , biochemistry , cell , membrane , enzyme , apoptosis , receptor
Sphingomyelinases (SMases) hydrolyze membrane sphingomyelin to ceramide and are ex‐pressed by diverse host and microbial cell types popu‐lating mucosal surfaces. Exogenous bacterial SMase acts on the basolateral membrane of polarized human intestinal epithelial cells to repress the cAMP‐induced Cl‐ secretory response, but how this occurs is un‐known. We show here that SMase acts by down‐regulating a cAMP‐gated basolateral membrane K + conduc‐tance. Neither phosphocholine, ceramide‐1‐phosphate, nor sphingosine‐1‐phosphate recapitulates this effect, indicating that ceramide production is the decisive factor. Basolaterally applied SMase induced the phos‐phorylation of c‐Jun NH 2 ‐terminal kinase (JNK), and inhibition of JNK rescued the effect of SMase on cAMP‐dependant secretion. SMase secreted by normal human fibroblasts specifically recapitulated the effect on cAMP‐induced Cl‐ secretion, indicating that cell types inhabiting the subepithelial space can provide such an activity to the basolateral membrane of intesti‐nal enterocytes in trans. Thus, conversion of sphingo‐myelin to ceramide in basolateral membranes of intes‐tinal cells rapidly activates JNK to inhibit a cAMP‐gated K + conductance and thereby attenuates Cl‐ secretion. These results define a novel lipid‐mediated pathway for regulation of salt and water homeostasis at mucosal surfaces.—Saslowsky, D. E., Tanaka, N., Reddy, K. P., Lencer, W. I. Ceramide activates JNK to inhibit a cAMP‐gated K + conductance and Cl‐ secretion in intestinal epithelia. FASEBJ. 23, 259‐270 (2009)