Normal mucus formation requires cAMP-dependent HCO3- secretion and Ca2+-mediated mucin exocytosis

J Physiol. 2013 Sep 15;591(18):4581-93. doi: 10.1113/jphysiol.2013.257436. Epub 2013 Jul 1.


Evidence from the pathology in cystic fibrosis (CF) and recent results in vitro indicate that HCO3- is required for gel-forming mucins to form the mucus that protects epithelial surfaces. Mucus formation and release is a complex process that begins with an initial intracellular phase of synthesis, packaging and apical granule exocytosis that is followed by an extracellular phase of mucin swelling, transport and discharge into a lumen. Exactly where HCO3- becomes crucial in these processes is unknown, but we observed that in the presence of HCO3-, stimulating dissected segments of native mouse intestine with 5-hydroxytryptamine (5-HT) and prostaglandin E2 (PGE2) induced goblet cell exocytosis followed by normal mucin discharge in wild-type (WT) intestines. CF intestines that inherently lack cystic fibrosis transmembrane conductance regulator (CFTR)-dependent HCO3- secretion also demonstrated apparently normal goblet cell exocytosis, but in contrast, this was not followed by similar mucin discharge. Moreover, we found that even in the presence of HCO3-, when WT intestines were stimulated only with a Ca2+-mediated agonist (carbachol), exocytosis was followed by poor discharge as with CF intestines. However, when the Ca2+-mediated agonist was combined with a cAMP-mediated agonist (isoproterenol (isoprenaline) or vasoactive intestinal peptide) in the presence of HCO3- both normal exocytosis and normal discharge was observed. These results indicate that normal mucus formation requires concurrent activation of a Ca2+-mediated exocytosis of mucin granules and an independent cAMP-mediated, CFTR-dependent, HCO3- secretion that appears to mainly enhance the extracellular phases of mucus excretion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bicarbonates / metabolism*
  • Calcium / metabolism*
  • Cyclic AMP / metabolism*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Dinoprostone / pharmacology
  • Exocytosis*
  • Goblet Cells / drug effects
  • Goblet Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CFTR
  • Mucins / metabolism*
  • Serotonin / pharmacology


  • Bicarbonates
  • Mucins
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Serotonin
  • Cyclic AMP
  • Dinoprostone
  • Calcium