HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 23, 20795-20801, June 6, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/23/20795    most recent M301638200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ahn, W. Articles by Muallem, S. Search for Related Content PubMed PubMed Citation Articles by Ahn, W. Articles by Muallem, S. Social Bookmarking                      What's this?

Multiple Effects of SERCA2b Mutations Associated with Darier's Disease^*

Wooin Ahn  , Min Goo Lee , Kyung Hwan Kim  and Shmuel Muallem  ¶

From the Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 and Department of Pharmacology and Brain Korea 21 Project for Medical Science, Yonsei University, Seoul 120-752, Korea

Darier's disease (DD) is an autosomal dominant disorder caused by mutations in the ATP2A2 gene, encoding sarco/endoplasmic reticulum Ca²⁺-ATPase pump type 2b isoform (SERCA2b). Although >100 mutations in the ATP2A2 gene were identified, no apparent relation between genotype/phenotype emerged. In this work, we analyzed 12 DD-associated mutations from all of the regions of SERCA2b to study the underlying pathologic mechanism of DD and to elucidate the role of dimerization in SERCA2b activity. Most mutations markedly affected protein expression, partially because of enhanced proteasome-mediated degradation. All of the mutants showed lower activity than the wild type pump. Notably, several mutants that cause relatively severe phenotype of DD inhibited the activity of the endogenous and the co-expressed wild type SERCA2b. Importantly, these effects were not attributed to changes in passive Ca²⁺ leak, inositol 1,4,5-trisphosphate receptor activity, or sensitivity to inositol 1,4,5-trisphosphate. Rather, co-immunoprecipitation experiments showed that SERCA2b monomers interact to influence the activity of each other. These findings reveal multiple molecular mechanisms to account for the plethora of pathologic states observed in DD and provide the first evidence for the importance of SERCA2b dimerization in pump function in vivo.

Received for publication, February 14, 2003

^* This work was supported by National Institutes of Health Grants DK38939 and DE13902 (to S. M.), Grant R02-2002-000-00052-0 from the Korea Science and Engineering Foundation (to M. G. L.), and a grant from the Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, Korea (to K. H. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Physiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas TX 75390-9040. E-mail: Shmuel.Muallem{at}UTSouthwestern.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. Sacchetto, S. Testoni, A. Gentile, E. Damiani, M. Rossi, R. Liguori, C. Drogemuller, and F. Mascarello A Defective SERCA1 Protein Is Responsible for Congenital Pseudomyotonia in Chianina Cattle Am. J. Pathol., February 1, 2009; 174(2): 565 - 573. [Abstract] [Full Text] [PDF]

				E. Vafiadaki, D. A. Arvanitis, S. N. Pagakis, V. Papalouka, D. Sanoudou, A. Kontrogianni-Konstantopoulos, and E. G. Kranias The Anti-apoptotic Protein HAX-1 Interacts with SERCA2 and Regulates Its Protein Levels to Promote Cell Survival Mol. Biol. Cell, January 1, 2009; 20(1): 306 - 318. [Abstract] [Full Text] [PDF]

				B. Pani, E. Cornatzer, W. Cornatzer, D.-M. Shin, M. R. Pittelkow, A. Hovnanian, I. S. Ambudkar, and B. B. Singh Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca2+ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease Mol. Biol. Cell, October 1, 2006; 17(10): 4446 - 4458. [Abstract] [Full Text] [PDF]

				Y. Miyauchi, T. Daiho, K. Yamasaki, H. Takahashi, A. Ishida-Yamamoto, S. Danko, H. Suzuki, and H. Iizuka Comprehensive Analysis of Expression and Function of 51 Sarco(endo)plasmic Reticulum Ca2+-ATPase Mutants Associated with Darier Disease J. Biol. Chem., August 11, 2006; 281(32): 22882 - 22895. [Abstract] [Full Text] [PDF]

				L. Foggia, I. Aronchik, K. Aberg, B. Brown, A. Hovnanian, and T. M. Mauro Activity of the hSPCA1 Golgi Ca2+ pump is essential for Ca2+-mediated Ca2+ response and cell viability in Darier disease J. Cell Sci., February 15, 2006; 119(4): 671 - 679. [Abstract] [Full Text] [PDF]

				B M Mayosi, A Kardos, C H Davies, F Gumedze, A Hovnanian, S Burge, and H Watkins Heterozygous disruption of SERCA2a is not associated with impairment of cardiac performance in humans: implications for SERCA2a as a therapeutic target in heart failure Heart, January 1, 2006; 92(1): 105 - 109. [Abstract] [Full Text] [PDF]

				K. Sato, K. Yamasaki, T. Daiho, Y. Miyauchi, H. Takahashi, A. Ishida-Yamamoto, S. Nakamura, H. Iizuka, and H. Suzuki Distinct Types of Abnormality in Kinetic Properties of Three Darier Disease-causing Sarco(endo)plasmic Reticulum Ca2+-ATPase Mutants That Exhibit Normal Expression and High Ca2+ Transport Activity J. Biol. Chem., August 20, 2004; 279(34): 35595 - 35603. [Abstract] [Full Text] [PDF]

				S. L. Chan, W. Fu, P. Zhang, A. Cheng, J. Lee, K. Kokame, and M. P. Mattson Herp Stabilizes Neuronal Ca2+ Homeostasis and Mitochondrial Function during Endoplasmic Reticulum Stress J. Biol. Chem., July 2, 2004; 279(27): 28733 - 28743. [Abstract] [Full Text] [PDF]

				Y. Li and P. Camacho Ca2+-dependent redox modulation of SERCA 2b by ERp57 J. Cell Biol., January 5, 2004; 164(1): 35 - 46. [Abstract] [Full Text] [PDF]

				L. Dode, J. P. Andersen, N. Leslie, J. Dhitavat, B. Vilsen, and A. Hovnanian Dissection of the Functional Differences between Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA) 1 and 2 Isoforms and Characterization of Darier Disease (SERCA2) Mutants by Steady-state and Transient Kinetic Analyses J. Biol. Chem., November 28, 2003; 278(48): 47877 - 47889. [Abstract] [Full Text] [PDF]

				T. Daiho, K. Yamasaki, G. Wang, S. Danko, H. Iizuka, and H. Suzuki Deletions of Any Single Residues in Glu40-Ser48 Loop Connecting A Domain and the First Transmembrane Helix of Sarcoplasmic Reticulum Ca2+-ATPase Result in Almost Complete Inhibition of Conformational Transition and Hydrolysis of Phosphoenzyme Intermediate J. Biol. Chem., October 3, 2003; 278(40): 39197 - 39204. [Abstract] [Full Text] [PDF]