title: AKAP2 anchors PKA with aquaporin-0 to support ocular lens transparency.
abstract: A decline in ocular lens transparency known as cataract afflicts 90% of individuals by the age 70. Chronic deterioration of lens tissue occurs as a pathophysiological consequence of defective water and nutrient circulation through channel and transporter proteins. A key component is the aquaporin-0 (AQP0) water channel whose permeability is tightly regulated in healthy lenses. Using a variety of cellular and biochemical approaches we have discovered that products of the A-kinase anchoring protein 2 gene (AKAP2/AKAP-KL) form a stable complex with AQP0 to sequester protein kinase A (PKA) with the channel. This permits PKA phosphorylation of serine 235 within a calmodulin (CaM)-binding domain of AQP0. The additional negative charge introduced by phosphoserine 235 perturbs electrostatic interactions between AQP0 and CaM to favour water influx through the channel. In isolated mouse lenses, displacement of PKA from the AKAP2-AQP0 channel complex promotes cortical cataracts as characterized by severe opacities and cellular damage. Thus, anchored PKA modulation of AQP0 is a homeostatic mechanism that must be physically intact to preserve lens transparency.
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Gold
authors.forename: Steve L
authors.initials: SL
authors.lastname: Reichow
authors.forename: Susan E
authors.initials: SE
authors.lastname: O'Neill
authors.forename: Chad R
authors.initials: CR
authors.lastname: Weisbrod
authors.forename: Lorene K
authors.initials: LK
authors.lastname: Langeberg
authors.forename: James E
authors.initials: JE
authors.lastname: Bruce
authors.forename: Tamir
authors.initials: T
authors.lastname: Gonen
authors.forename: John D
authors.initials: JD
authors.lastname: Scott
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000818:Animals; D020346:Aquaporins / Q000737:chemistry / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D002386:Cataract / Q000378:metabolism / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005136:Eye Proteins / Q000737:chemistry / Q000378:metabolism*; D007908:Lens, Crystalline / Q000201:enzymology / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010748:Phosphopeptides / Q000032:analysis; D010766:Phosphorylation; D011485:Protein Binding; D012756:Sheep; D055672:Static Electricity; D014867:Water / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; D020346:Aquaporins; D002147:Calmodulin; D005136:Eye Proteins; D008565:Membrane Proteins; C111169:Pakap protein, mouse; D010748:Phosphopeptides; C030328:aquaporin 0; D014867:Water; D017868:Cyclic AMP-Dependent Protein Kinases
references.citation: Mol Vis. 2007 Sep 30;13:1822-7
references.pmid: 17960133
references.citation: Bull World Health Organ. 2001;79(3):249-56
references.pmid: 11285671
references.citation: Science. 1995 Jan 6;267(5194):108-11
references.pmid: 7528941
references.citation: EMBO J. 2001 Apr 17;20(8):1921-30
references.pmid: 11296225
references.citation: J Biol Chem. 1998 Mar 13;273(11):6533-41
references.pmid: 9497389
references.citation: J Membr Biol. 2007 Mar;216(1):1-16
references.pmid: 17568975
references.citation: Invest Ophthalmol Vis Sci. 2010 May;51(5):2303-6
references.pmid: 20435604
references.citation: Biochemistry. 2004 Aug 3;43(30):9856-65
references.pmid: 15274640
references.citation: Biochemistry. 2008 Jan 8;47(1):339-47
references.pmid: 18081321
references.citation: Mol Cell. 2006 Nov 3;24(3):397-408
references.pmid: 17081990
references.citation: Biochim Biophys Acta. 2004 Mar 23;1662(1-2):96-101
references.pmid: 15033581
references.citation: Biochem Biophys Res Commun. 2001 Aug 3;285(5):1369-76
references.pmid: 11478809
references.citation: Science. 2009 Nov 27;326(5957):1220-4
references.pmid: 19965465
references.citation: J Gen Physiol. 2004 May;123(5):573-80
references.pmid: 15078916
references.citation: Exp Eye Res. 2003 Jan;76(1):61-70
references.pmid: 12589776
references.citation: Nat Genet. 2000 May;25(1):15-7
references.pmid: 10802646
references.citation: J Comput Chem. 2004 Oct;25(13):1605-12
references.pmid: 15264254
references.citation: Q Rev Biophys. 2006 Nov;39(4):361-96
references.pmid: 17156589
references.citation: Science. 1993 Dec 10;262(5140):1718-21
references.pmid: 8259515
references.citation: Nat Cell Biol. 2010 Dec;12(12):1242-9
references.pmid: 21102438
references.citation: J Biol Chem. 2001 Jun 22;276(25):21999-2002
references.pmid: 11285255
references.citation: J Proteome Res. 2006 Jan;5(1):112-21
references.pmid: 16396501
references.citation: FEBS Lett. 1982 Mar 22;139(2):287-90
references.pmid: 6281068
references.citation: Physiol Rev. 2010 Jan;90(1):179-206
references.pmid: 20086076
references.citation: Invest Ophthalmol Vis Sci. 2010 May;51(5):2306-10; discussion 2310-2
references.pmid: 20435605
references.citation: Mol Vis. 2007 Sep 11;13:1651-6
references.pmid: 17893667
references.citation: Nature. 2005 Sep 22;437(7058):574-8
references.pmid: 16177794
references.citation: J Biol Chem. 2008 Jul 25;283(30):21278-83
references.pmid: 18508773
references.citation: Invest Ophthalmol Vis Sci. 2005 Apr;46(4):1393-402
references.pmid: 15790907
references.citation: J Biol Chem. 1992 Aug 25;267(24):16816-23
references.pmid: 1512224
references.citation: Cell Differ. 1972 Jun;1(2):91-106
references.pmid: 4275925
references.citation: Br J Ophthalmol. 2000 Dec;84(12):1376-9
references.pmid: 11090476
references.citation: J Biol Chem. 1997 Feb 21;272(8):4747-52
references.pmid: 9030527
references.citation: Nature. 2005 Dec 1;438(7068):633-8
references.pmid: 16319884
references.citation: Mol Cell. 2006 Nov 3;24(3):383-95
references.pmid: 17081989
references.citation: Science. 1996 Mar 15;271(5255):1589-92
references.pmid: 8599116
references.citation: Structure. 2008 Sep 10;16(9):1389-98
references.pmid: 18786401
references.citation: Nature. 2004 May 13;429(6988):193-7
references.pmid: 15141214