title: Clcn2 encodes the hyperpolarization-activated chloride channel in the ducts of mouse salivary glands.
abstract: Transepithelial Cl(-) transport in salivary gland ducts is a major component of the ion reabsorption process, the final stage of saliva production. It was previously demonstrated that a Cl(-) current with the biophysical properties of ClC-2 channels dominates the Cl(-) conductance of unstimulated granular duct cells in the mouse submandibular gland. This inward-rectifying Cl(-) current is activated by hyperpolarization and elevated intracellular Cl(-) concentration. Here we show that ClC-2 immunolocalized to the basolateral region of acinar and duct cells in mouse salivary glands, whereas its expression was most robust in granular and striated duct cells. Consistent with this observation, nearly 10-fold larger ClC-2-like currents were observed in granular duct cells than the acinar cells obtained from submandibular glands. The loss of inward-rectifying Cl(-) current in cells from Clcn2(-/-) mice confirmed the molecular identity of the channel responsible for these currents as ClC-2. Nevertheless, both in vivo and ex vivo fluid secretion assays failed to identify significant changes in the ion composition, osmolality, or salivary flow rate of Clcn2(-/-) mice. Additionally, neither a compensatory increase in Cftr Cl(-) channel protein expression nor in Cftr-like Cl(-) currents were detected in Clcn2 null mice, nor did it appear that ClC-2 was important for blood-organ barrier function. We conclude that ClC-2 is the inward-rectifying Cl(-) channel in duct cells, but its expression is not apparently required for the ion reabsorption or the barrier function of salivary ductal epithelium.
authors.affiliation: Center for Oral Biology, Univ. of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Victor G
authors.initials: VG
authors.lastname: Romanenko
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Nakamoto
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Catalán
authors.forename: Mireya
authors.initials: M
authors.lastname: Gonzalez-Begne
authors.forename: George J
authors.initials: GJ
authors.lastname: Schwartz
authors.forename: Yasna
authors.initials: Y
authors.lastname: Jaramillo
authors.forename: Francisco V
authors.initials: FV
authors.lastname: Sepúlveda
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Figueroa
authors.forename: James E
authors.initials: JE
authors.lastname: Melvin
mesh_terms: D000818:Animals; D000090007:CLC-2 Chloride Channels; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004594:Electrophysiology; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D012469:Salivary Glands / Q000166:cytology / Q000378:metabolism*; D012965:Sodium Chloride / Q000378:metabolism; D013995:Time
chemical_list: D000090007:CLC-2 Chloride Channels; D018118:Chloride Channels; C000715428:Clcn2 protein, mouse; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012965:Sodium Chloride
references.citation: Curr Opin Nephrol Hypertens. 2008 May;17(3):320-5
references.pmid: 18408486
references.citation: J Biol Chem. 2002 Jun 28;277(26):23604-11
references.pmid: 11976342
references.citation: EMBO J. 2001 Mar 15;20(6):1289-99
references.pmid: 11250895
references.citation: Am J Physiol Cell Physiol. 2002 Apr;282(4):C805-16
references.pmid: 11880269
references.citation: Gastroenterology. 2004 Apr;126(4):1104-14
references.pmid: 15057749
references.citation: Kidney Int. 2006 Jun;69(11):2070-7
references.pmid: 16612328
references.citation: Am J Physiol Regul Integr Comp Physiol. 2008 May;294(5):R1729-36
references.pmid: 18337312
references.citation: Physiol Rev. 2002 Apr;82(2):503-68
references.pmid: 11917096
references.citation: Am J Physiol Cell Physiol. 2001 Jun;280(6):C1599-606
references.pmid: 11350755
references.citation: Am J Physiol Cell Physiol. 2004 Nov;287(5):C1173-83
references.pmid: 15213059
references.citation: Annu Rev Physiol. 2005;67:445-69
references.pmid: 15709965
references.citation: J Physiol. 2007 Jun 1;581(Pt 2):801-17
references.pmid: 17379640
references.citation: Pflugers Arch. 1994 Oct;428(3-4):202-8
references.pmid: 7529397
references.citation: Rev Physiol Biochem Pharmacol. 2007;158:23-76
references.pmid: 17729441
references.citation: Am J Physiol Cell Physiol. 2002 Oct;283(4):C1206-18
references.pmid: 12225984
references.citation: J Auton Nerv Syst. 1984 Nov;11(3):233-41
references.pmid: 6512169
references.citation: Am J Physiol Cell Physiol. 2008 Mar;294(3):C810-9
references.pmid: 18216162
references.citation: Am J Physiol. 1973 Jan;224(1):136-9
references.pmid: 4683291
references.citation: Nat Genet. 2003 Apr;33(4):527-32
references.pmid: 12612585
references.citation: Am J Physiol. 1991 Sep;261(3 Pt 1):C490-6
references.pmid: 1716052
references.citation: Pflugers Arch. 1994 Oct;428(5-6):641-7
references.pmid: 7838687
references.citation: Nature. 1992 Mar 5;356(6364):57-60
references.pmid: 1311421
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Feb;292(2):G647-56
references.pmid: 17053162
references.citation: J Dent Res. 2006 Dec;85(12):1101-5
references.pmid: 17122162
references.citation: J Biol Chem. 2000 Sep 1;275(35):26720-6
references.pmid: 10831596
references.citation: J Membr Biol. 1993 Sep;135(3):289-95
references.pmid: 8271268
references.citation: J Gen Physiol. 2005 Dec;126(6):591-603
references.pmid: 16286506
references.citation: Crit Rev Oral Biol Med. 1999;10(2):199-209
references.pmid: 10759422
references.citation: Dig Dis Sci. 2001 Jan;46(1):208-13
references.pmid: 11270788
references.citation: Biochim Biophys Acta. 2007 Jan;1772(1):15-20
references.pmid: 17156979
references.citation: Exp Physiol. 1993 Jan;78(1):49-64
references.pmid: 8383503
references.citation: Am J Physiol. 1995 May;268(5 Pt 1):G806-12
references.pmid: 7539220
references.citation: Epilepsy Res. 2007 Jul;75(2-3):145-53
references.pmid: 17580110
references.citation: Am J Physiol Gastrointest Liver Physiol. 2002 Oct;283(4):G1004-13
references.pmid: 12223361
references.citation: Am J Physiol. 1997 Aug;273(2 Pt 1):C442-55
references.pmid: 9277342
references.citation: J Biol Chem. 1997 Dec 26;272(52):32956-65
references.pmid: 9407075
references.citation: Nature. 2006 Mar 23;440(7083):484-9
references.pmid: 16554809
references.citation: J Biol Chem. 1999 Sep 17;274(38):26946-55
references.pmid: 10480906
references.citation: J Cell Sci. 2005 Sep 15;118(Pt 18):4243-52
references.pmid: 16155254
references.citation: Am J Physiol Lung Cell Mol Physiol. 2000 Jun;278(6):L1248-55
references.pmid: 10835331
references.citation: Annu Rev Physiol. 2005;67:779-807
references.pmid: 15709978
references.citation: J Neurosci. 2007 Jun 13;27(24):6581-9
references.pmid: 17567819
references.citation: Gastroenterology. 2004 Sep;127(3):802-15
references.pmid: 15362036
references.citation: J Physiol. 1996 Jan 15;490 ( Pt 2):351-62
references.pmid: 8821134