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This Article Full Text Full Text (PDF) All Versions of this Article: fj.08-116467v1 23/1/259    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Saslowsky, D. E. Articles by Lencer, W. I. Search for Related Content PubMed PubMed Citation Articles by Saslowsky, D. E. Articles by Lencer, W. I.

Ceramide activates JNK to inhibit a cAMP-gated K⁺ conductance and Cl^– secretion in intestinal epithelia

David E. Saslowsky^*,,1, Noriyuki Tanaka, Krishna P. Reddy and Wayne I. Lencer^*

^* GI Cell Biology, Children’s Hospital, and the Harvard Digestive Diseases Center, Boston, Massachusetts, USA;

Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA; and

Teine Keijinkai Hospital, Sapporo, Japan

¹ Correspondence: Children’s Hospital, 300 Longwood Ave., Enders 720, Boston, MA 02115, USA. E-mail: david.saslowsky{at}childrens.harvard.edu

Sphingomyelinases (SMases) hydrolyze membrane sphingomyelin to ceramide and are expressed by diverse host and microbial cell types populating 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 unknown. We show here that SMase acts by down-regulating a cAMP-gated basolateral membrane K⁺ conductance. 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 phosphorylation of c-Jun NH₂-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 intestinal enterocytes in trans. Thus, conversion of sphingomyelin to ceramide in basolateral membranes of intestinal 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.

Key Words: sphingomyelinase • sphingomyelin • potassium channel