Tags

Type your tag names separated by a space and hit enter

Essential role of carbonic anhydrase XII in secretory gland fluid and HCO3 (-) secretion revealed by disease causing human mutation.
J Physiol 2015; 593(24):5299-312JP

Abstract

KEY POINTS

Fluid and HCO3 (-) 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 HCO3 (-) secretion and works by activating the ductal Cl(-) -HCO3 (-) 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 HCO3 (-) secretion is associated with many diseases. The activity of HCO3 (-) transporters depends of HCO3 (-) 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 HCO3 (-) supplier of ductal Cl(-) -HCO3 (-) 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.

Authors+Show Affiliations

Epithelial Signalling and Transport Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA. Department of Physiology, College of Medicine, Gachon University, 191 Hambakmeoro, Yeonsu-gu, Incheon, 406-799, South Korea.Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Beer Sheva, Israel.Epithelial Signalling and Transport Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA.Pediatric Endocrinology Unit, Soroka Medical Centre and Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.Pediatric Endocrinology Unit, Soroka Medical Centre and Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.Pediatric Endocrinology Unit, Soroka Medical Centre and Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Beer Sheva, Israel.Epithelial Signalling and Transport Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26486891

Citation

Hong, Jeong Hee, et al. "Essential Role of Carbonic Anhydrase XII in Secretory Gland Fluid and HCO3 (-) Secretion Revealed By Disease Causing Human Mutation." The Journal of Physiology, vol. 593, no. 24, 2015, pp. 5299-312.
Hong JH, Muhammad E, Zheng C, et al. Essential role of carbonic anhydrase XII in secretory gland fluid and HCO3 (-) secretion revealed by disease causing human mutation. J Physiol (Lond). 2015;593(24):5299-312.
Hong, J. H., Muhammad, E., Zheng, C., Hershkovitz, E., Alkrinawi, S., Loewenthal, N., ... Muallem, S. (2015). Essential role of carbonic anhydrase XII in secretory gland fluid and HCO3 (-) secretion revealed by disease causing human mutation. The Journal of Physiology, 593(24), pp. 5299-312. doi:10.1113/JP271378.
Hong JH, et al. Essential Role of Carbonic Anhydrase XII in Secretory Gland Fluid and HCO3 (-) Secretion Revealed By Disease Causing Human Mutation. J Physiol (Lond). 2015 Dec 15;593(24):5299-312. PubMed PMID: 26486891.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Essential role of carbonic anhydrase XII in secretory gland fluid and HCO3 (-) secretion revealed by disease causing human mutation. AU - Hong,Jeong Hee, AU - Muhammad,Emad, AU - Zheng,Changyu, AU - Hershkovitz,Eli, AU - Alkrinawi,Soliman, AU - Loewenthal,Neta, AU - Parvari,Ruti, AU - Muallem,Shmuel, Y1 - 2015/12/07/ PY - 2015/07/28/received PY - 2015/10/12/accepted PY - 2015/10/22/entrez PY - 2015/10/22/pubmed PY - 2016/10/7/medline SP - 5299 EP - 312 JF - The Journal of physiology JO - J. Physiol. (Lond.) VL - 593 IS - 24 N2 - KEY POINTS: Fluid and HCO3 (-) 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 HCO3 (-) secretion and works by activating the ductal Cl(-) -HCO3 (-) 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 HCO3 (-) secretion is associated with many diseases. The activity of HCO3 (-) transporters depends of HCO3 (-) 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 HCO3 (-) supplier of ductal Cl(-) -HCO3 (-) 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. SN - 1469-7793 UR - https://www.unboundmedicine.com/medline/citation/26486891/Essential_role_of_carbonic_anhydrase_XII_in_secretory_gland_fluid_and_HCO3_____secretion_revealed_by_disease_causing_human_mutation_ L2 - https://doi.org/10.1113/JP271378 DB - PRIME DP - Unbound Medicine ER -