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TMEM16A and NHERF1 Regulate Ca2+ and cAMP Stimulated Cl‐ Secretion in Murine Colon
Author(s) -
Kazi Mirajul Hoque,
Ali Irshad,
Sarker Rafiquel,
Cha Boyoung,
Zachos Nicholas C,
Harfe Brain D,
Donowitz Mark,
Tse Chung Ming
Publication year - 2012
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/fasebj.26.1_supplement.1111.1
Subject(s) - secretion , basal (medicine) , chemistry , medicine , endocrinology , ussing chamber , carbachol , chloride channel , biology , stimulation , biochemistry , insulin
TMEM16A is a calcium activated chloride channel (CaCC). However, its role in colonic Cl secretion is unknown. By qPCR, we identified TMEM16A as the predominant CaCC in mouse colon and hypothesized that it was involved in basal and Ca 2+ ‐ stimulated colonic Cl secretion. Because the NHERF family of PDZ domain containing proteins has been shown to regulate intestinal ion transporters, we tested whether NHERF1 and NHERF2 are involved in TMEM16A regulation. Colonic Cl secretion was measured as the change in short circuit current (ΔIsc) by Ussing chamber. Digallic acid, a CaCC inhibitor inhibited basal Isc by 50% (p<0.05) and completely abolished carbachol (CCH) stimulated Isc in the wild type (WT) mouse colon. In TMEM16A+/− colon, basal, CCH and forskolin (FSK) stimulated Isc were reduced by 47% (p<0.04), 67% (p<0.001) and 75% (p<0.001), respectively. In NHERF1−/− mice, basal and CCH stimulated Isc were reduced by 60% (P<0.01) and 92% (P<0.001), while there was no significant change in the FSK stimulated Isc. Basal, CCH and FSK stimulated Isc in NHERF2−/− colonic tissues were not different from WT. Our results suggest that in mouse colon (1) TMEM16A is a major contributor of basal, CCH and unexpectedly also cAMP stimulated Cl secretion; (2) NHERF1, but not NHERF2 plays an important role in basal and CCH stimulated Cl secretion. In conclusion, NHERF1 affects colonic Cl secretion via effects on TMEM16A.