title: Homer2 protein regulates plasma membrane Ca²⁺-ATPase-mediated Ca²⁺ signaling in mouse parotid gland acinar cells.
abstract: Homer proteins are scaffold molecules with a domain structure consisting of an N-terminal Ena/VASP homology 1 protein-binding domain and a C-terminal leucine zipper/coiled-coil domain. The Ena/VASP homology 1 domain recognizes proline-rich motifs and binds multiple Ca(2+)-signaling proteins, including G protein-coupled receptors, inositol 1,4,5-triphosphate receptors, ryanodine receptors, and transient receptor potential channels. However, their role in Ca(2+) signaling in nonexcitable cells is not well understood. In this study, we investigated the role of Homer2 on Ca(2+) signaling in parotid gland acinar cells using Homer2-deficient (Homer2(-/-)) mice. Homer2 is localized at the apical pole in acinar cells. Deletion of Homer2 did not affect inositol 1,4,5-triphosphate receptor localization or channel activity and did not affect the expression and activity of sarco/endoplasmic reticulum Ca(2+)-ATPase pumps. In contrast, Homer2 deletion markedly increased expression of plasma membrane Ca(2+)-ATPase (PMCA) pumps, in particular PMCA4, at the apical pole. Accordingly, Homer2 deficiency increased Ca(2+) extrusion by acinar cells. These findings were supported by co-immunoprecipitation of Homer2 and PMCA in wild-type parotid cells and transfected human embryonic kidney 293 (HEK293) cells. We identified a Homer-binding PPXXF-like motif in the N terminus of PMCA that is required for interaction with Homer2. Mutation of the PPXXF-like motif did not affect the interaction of PMCA with Homer1 but inhibited its interaction with Homer2 and increased Ca(2+) clearance by PMCA. These findings reveal an important regulation of PMCA by Homer2 that has a central role on PMCA-mediated Ca(2+) signaling in parotid acinar cells.
authors: From the Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Korea.
authors: Yu-Mi
authors: YM
authors: Yang
authors: From the Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Korea.
authors: Jiae
authors: J
authors: Lee
authors: the College of Life Sciences and Graduate School of Biotechnology, Kyunghee University, Global Campus, Gyeonggi 446-701, Korea, and.
authors: Hae
authors: H
authors: Jo
authors: From the Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Korea.
authors: Soonhong
authors: S
authors: Park
authors: From the Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Korea.
authors: Inik
authors: I
authors: Chang
authors: the Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892.
authors: Shmuel
authors: S
authors: Muallem
authors: From the Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Korea, dmshin@yuhs.ac.
authors: Dong Min
authors: DM
authors: Shin
mesh_terms: D061354:Acinar Cells / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D000072233:Homer Scaffolding Proteins; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010306:Parotid Gland / Q000166:cytology / Q000378:metabolism*; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D002352:Carrier Proteins; C000606614:HOMER1 protein, human; D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse; C000606625:Homer2 protein, mouse; D053496:Inositol 1,4,5-Trisphosphate Receptors; D053499:Plasma Membrane Calcium-Transporting ATPases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D002118:Calcium
keywords: Calcium ATPase; Calcium Transport; Cell Signaling; Homer Proteins; Parotid Gland; Plasma Membrane Ca2+-ATPase; Proline-rich Motif; Protein-Protein Interaction; Scaffold Protein