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Essential role of carbonic anhydrase XII in secretory gland fluid and HCO 3 − secretion revealed by disease causing human mutation
Author(s) -
Hong Jeong Hee,
Muhammad Emad,
Zheng Changyu,
Hershkovitz Eli,
Alkrinawi Soliman,
Loewenthal Neta,
Parvari Ruti,
Muallem Shmuel
Publication year - 2015
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp271378
Subject(s) - secretion , carbonic anhydrase , sodium–hydrogen antiporter , carbonic anhydrase ii , medicine , chemistry , endocrinology , biology , microbiology and biotechnology , biochemistry , enzyme , sodium , organic chemistry
Key points Fluid and HCO 3 − secretion is essential for all epithelia; aberrant secretion is associated with several diseases. Carbonic anhydrase XII (CA12) is the key carbonic anhydrase in epithelial fluid and HCO 3 − secretion and works by activating the ductal Cl − –HCO 3 − exchanger AE2. Delivery of CA12 to salivary glands increases salivation in mice and of the human mutation CA12(E143K) markedly inhibits it. The human mutation CA12(E143K) causes disease due to aberrant CA12 glycosylation, and misfolding resulting in loss of AE2 activity.Abstract Aberrant epithelial fluid and HCO 3 − secretion is associated with many diseases. The activity of HCO 3 − transporters depends of HCO 3 − availability that is determined by carbonic anhydrases (CAs). Which CAs are essential for epithelial function is unknown. CA12 stands out since the CA12(E143K) mutation causes salt wasting in sweat and dehydration in humans. Here, we report that expression of CA12 and of CA12(E143K) in mice salivary glands respectively increased and prominently inhibited ductal fluid secretion and salivation in vivo . CA12 markedly increases the activity and is the major HCO 3 − supplier of ductal Cl − –HCO 3 − exchanger AE2, but not of NBCe1‐B. The E143K mutation alters CA12 glycosylation at N28 and N80, resulting in retention of the basolateral CA12 in the ER. Knockdown of AE2 and of CA12 inhibited pancreatic and salivary gland ductal AE2 activity and fluid secretion. Accordingly, patients homozygous for the CA12(E143K) mutation have a dry mouth, dry tongue phenotype. These findings reveal an unsuspected prominent role of CA12 in epithelial function, explain the disease and call for caution in the use of CA12 inhibitors in cancer treatment.