Ae4 (Slc4a9) Anion Exchanger Drives Cl- Uptake-dependent Fluid Secretion by Mouse Submandibular Gland Acinar Cells.
Transcellular Cl(-) movement across acinar cells is the rate-limiting step for salivary gland fluid secretion. Basolateral Nkcc1 Na(+)-K(+)-2Cl(-) cotransporters play a critical role in fluid secretion by promoting the intracellular accumulation of Cl(-) above its equilibrium potential. However, salivation is only partially abolished in the absence of Nkcc1 cotransporter activity, suggesting that another Cl(-) uptake pathway concentrates Cl(-) ions in acinar cells. To identify alternative molecular mechanisms, we studied mice lacking Ae2 and Ae4 Cl(-)/HCO3 (-) exchangers. We found that salivation stimulated by muscarinic and β-adrenergic receptor agonists was normal in the submandibular glands of Ae2(-/-) mice. In contrast, saliva secretion was reduced by 35% in Ae4(-/-) mice. The decrease in salivation was not related to loss of Na(+)-K(+)-2Cl(-) cotransporter or Na(+)/H(+) exchanger activity in Ae4(-/-) mice but correlated with reduced Cl(-) uptake during β-adrenergic receptor activation of cAMP signaling. Direct measurements of Cl(-)/HCO3 (-) exchanger activity revealed that HCO3 (-)-dependent Cl(-) uptake was reduced in the acinar cells of Ae2(-/-) and Ae4(-/-) mice. Moreover, Cl(-)/HCO3 (-) exchanger activity was nearly abolished in double Ae4/Ae2 knock-out mice, suggesting that most of the Cl(-)/HCO3 (-) exchanger activity in submandibular acinar cells depends on Ae2 and Ae4 expression. In conclusion, both Ae2 and Ae4 anion exchangers are functionally expressed in submandibular acinar cells; however, only Ae4 expression appears to be important for cAMP-dependent regulation of fluid secretion.
From the Secretory Mechanisms and Dysfunction Section, Division of Intramural Research, NIDCR, National Institutes of Health, Bethesda, Maryland 20892.
Gaspar
G
Peña-Münzenmayer
From the Secretory Mechanisms and Dysfunction Section, Division of Intramural Research, NIDCR, National Institutes of Health, Bethesda, Maryland 20892.
Marcelo A
MA
Catalán
From the Secretory Mechanisms and Dysfunction Section, Division of Intramural Research, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, the Department of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Kitakyushu, Fukuoka, Japan.
Yusuke
Y
Kondo
From the Secretory Mechanisms and Dysfunction Section, Division of Intramural Research, NIDCR, National Institutes of Health, Bethesda, Maryland 20892.
Yasna
Y
Jaramillo
From the Secretory Mechanisms and Dysfunction Section, Division of Intramural Research, NIDCR, National Institutes of Health, Bethesda, Maryland 20892.
Frances
F
Liu
the Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, and.
Gary E
GE
Shull
From the Secretory Mechanisms and Dysfunction Section, Division of Intramural Research, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, james.melvin@nih.gov.
James E
JE
Melvin
D061354:Acinar Cells / Q000378:metabolism*; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D027963:Chloride-Bicarbonate Antiporters / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D017136:Ion Transport; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012463:Saliva / Q000378:metabolism; D013363:Submandibular Gland / Q000166:cytology / Q000378:metabolism*
D001639:Bicarbonates; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; C579495:Slc4a2 protein, mouse; C480025:Slc4a9 protein, mouse; D000242:Cyclic AMP
Bicarbonate; Chloride Transport; Epithelium; Exchanger; Salivary Gland; Secretion