Homer2 Protein Regulates Plasma Membrane Ca2+-ATPase-mediated Ca2+ Signaling in Mouse Parotid Gland Acinar Cells |
| |
Authors: | Yu-Mi Yang Jiae Lee Hae Jo Soonhong Park Inik Chang Shmuel Muallem Dong Min Shin |
| |
Institution: | From the ‡Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Korea.;the §College of Life Sciences and Graduate School of Biotechnology, Kyunghee University, Global Campus, Gyeonggi 446-701, Korea, and ;the ¶Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892 |
| |
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 Ca2+-signaling proteins, including G protein-coupled receptors, inositol 1,4,5-triphosphate receptors, ryanodine receptors, and transient receptor potential channels. However, their role in Ca2+ signaling in nonexcitable cells is not well understood. In this study, we investigated the role of Homer2 on Ca2+ 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 Ca2+-ATPase pumps. In contrast, Homer2 deletion markedly increased expression of plasma membrane Ca2+-ATPase (PMCA) pumps, in particular PMCA4, at the apical pole. Accordingly, Homer2 deficiency increased Ca2+ 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 Ca2+ clearance by PMCA. These findings reveal an important regulation of PMCA by Homer2 that has a central role on PMCA-mediated Ca2+ signaling in parotid acinar cells. |
| |
Keywords: | Calcium ATPase Calcium Transport Cell Signaling Protein-Protein Interaction Scaffold Protein Homer Proteins Plasma Membrane Ca2+-ATPase Parotid Gland Proline-rich Motif |
|
|