Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 330 (6000): 105-109

Copyright © 2010 by the American Association for the Advancement of Science

The Calcium Store Sensor, STIM1, Reciprocally Controls Orai and CaV1.2 Channels

Youjun Wang,1 Xiaoxiang Deng,1,* Salvatore Mancarella,1,* Eunan Hendron,1,* Satoru Eguchi,2 Jonathan Soboloff,1 Xiang D. Tang,3 Donald L. Gill1,{dagger}

Abstract: Calcium signals, pivotal in controlling cell function, can be generated by calcium entry channels activated by plasma membrane depolarization or depletion of internal calcium stores. We reveal a regulatory link between these two channel subtypes mediated by the ubiquitous calcium-sensing STIM proteins. STIM1 activation by store depletion or mutational modification strongly suppresses voltage-operated calcium (CaV1.2) channels while activating store-operated Orai channels. Both actions are mediated by the short STIM-Orai activating region (SOAR) of STIM1. STIM1 interacts with CaV1.2 channels and localizes within discrete endoplasmic reticulum/plasma membrane junctions containing both CaV1.2 and Orai1 channels. Hence, STIM1 interacts with and reciprocally controls two major calcium channels hitherto thought to operate independently. Such coordinated control of the widely expressed CaV1.2 and Orai channels has major implications for Ca2+ signal generation in excitable and nonexcitable cells.

1 Department of Biochemistry and Cardiovascular Research Center, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140, USA.
2 Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
3 Department of Pharmacology, Nankai University School of Medicine, Tianjin 300071, China.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: dgill{at}

Age- and location-dependent differences in store depletion-induced h-channel plasticity in hippocampal pyramidal neurons.
A. M. Clemens and D. Johnston (2014)
J Neurophysiol 111, 1369-1382
   Abstract »    Full Text »    PDF »
Activation of the Endoplasmic Reticulum Calcium Sensor STIM1 and Store-Operated Calcium Entry by Rotavirus Requires NSP4 Viroporin Activity.
J. M. Hyser, B. Utama, S. E. Crawford, J. R. Broughman, and M. K. Estes (2013)
J. Virol. 87, 13579-13588
   Abstract »    Full Text »    PDF »
Urotensin-II promotes vascular smooth muscle cell proliferation through store-operated calcium entry and EGFR transactivation.
M. Rodriguez-Moyano, I. Diaz, N. Dionisio, X. Zhang, J. Avila-Medina, E. Calderon-Sanchez, M. Trebak, J. A. Rosado, A. Ordonez, and T. Smani (2013)
Cardiovasc Res 100, 297-306
   Abstract »    Full Text »    PDF »
Ca2+ Influx through Store-operated Ca2+ Channels Reduces Alzheimer Disease {beta}-Amyloid Peptide Secretion.
W. Zeiger, K. S. Vetrivel, V. Buggia-Prevot, P. D. Nguyen, S. L. Wagner, M. L. Villereal, and G. Thinakaran (2013)
J. Biol. Chem. 288, 26955-26966
   Abstract »    Full Text »    PDF »
STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology.
H. E. Collins, X. Zhu-Mauldin, R. B. Marchase, and J. C. Chatham (2013)
Am J Physiol Heart Circ Physiol 305, H446-H458
   Abstract »    Full Text »    PDF »
A TRPC1 Protein-dependent Pathway Regulates Osteoclast Formation and Function.
E.-C. Ong, V. Nesin, C. L. Long, C.-X. Bai, J. L. Guz, I. P. Ivanov, J. Abramowitz, L. Birnbaumer, M. B. Humphrey, and L. Tsiokas (2013)
J. Biol. Chem. 288, 22219-22232
   Abstract »    Full Text »    PDF »
Phosphorylation of STIM1 at ERK1/2 target sites regulates interaction with the microtubule plus-end binding protein EB1.
E. Pozo-Guisado, V. Casas-Rua, P. Tomas-Martin, A. M. Lopez-Guerrero, A. Alvarez-Barrientos, and F. J. Martin-Romero (2013)
J. Cell Sci. 126, 3170-3180
   Abstract »    Full Text »    PDF »
Exome Sequencing and Systems Biology Converge to Identify Novel Mutations in the L-Type Calcium Channel, CACNA1C, Linked to Autosomal Dominant Long QT Syndrome.
N. J. Boczek, J. M. Best, D. J. Tester, J. R. Giudicessi, S. Middha, J. M. Evans, T. J. Kamp, and M. J. Ackerman (2013)
Circ Cardiovasc Genet 6, 279-289
   Abstract »    Full Text »    PDF »
Differential Roles of the C and N Termini of Orai1 Protein in Interacting with Stromal Interaction Molecule 1 (STIM1) for Ca2+ Release-activated Ca2+ (CRAC) Channel Activation.
H. Zheng, M.-H. Zhou, C. Hu, E. Kuo, X. Peng, J. Hu, L. Kuo, and S. L. Zhang (2013)
J. Biol. Chem. 288, 11263-11272
   Abstract »    Full Text »    PDF »
New Horizons in Cellular Regulation by Inositol Polyphosphates: Insights from the Pancreatic {beta}-Cell.
C. J. Barker and P.-O. Berggren (2013)
Pharmacol. Rev. 65, 641-669
   Abstract »    Full Text »    PDF »
Orai1 Function Is Essential for T Cell Homing to Lymph Nodes.
M. L. Greenberg, Y. Yu, S. Leverrier, S. L. Zhang, I. Parker, and M. D. Cahalan (2013)
J. Immunol. 190, 3197-3206
   Abstract »    Full Text »    PDF »
Quantitative interactions between the A-type K+ current and inositol trisphosphate receptors regulate intraneuronal Ca2+ waves and synaptic plasticity.
S. Ashhad and R. Narayanan (2013)
J. Physiol. 591, 1645-1669
   Abstract »    Full Text »    PDF »
Targeted STIM deletion impairs calcium homeostasis, NFAT activation, and growth of smooth muscle.
S. Mancarella, S. Potireddy, Y. Wang, H. Gao, R. K. Gandhirajan, M. Autieri, R. Scalia, Z. Cheng, H. Wang, M. Madesh, et al. (2013)
FASEB J 27, 893-906
   Abstract »    Full Text »    PDF »
Modification of STIM1 by O-linked N-Acetylglucosamine (O-GlcNAc) Attenuates Store-operated Calcium Entry in Neonatal Cardiomyocytes.
X. Zhu-Mauldin, S. A. Marsh, L. Zou, R. B. Marchase, and J. C. Chatham (2012)
J. Biol. Chem. 287, 39094-39106
   Abstract »    Full Text »    PDF »
ROS and SOCE: recent advances and controversies in the regulation of STIM and Orai.
I. Bogeski, T. Kilch, and B. A. Niemeyer (2012)
J. Physiol. 590, 4193-4200
   Abstract »    Full Text »    PDF »
STIM/Orai signalling complexes in vascular smooth muscle.
M. Trebak (2012)
J. Physiol. 590, 4201-4208
   Abstract »    Full Text »    PDF »
Orai1, STIM1, and their associating partners.
S. Srikanth and Y. Gwack (2012)
J. Physiol. 590, 4169-4177
   Abstract »    Full Text »    PDF »
L-Type Calcium Channels: On the Fast Track to Nuclear Signaling.
M. D'Arco and A. C. Dolphin (2012)
Science Signaling 5, pe34
   Abstract »    Full Text »    PDF »
STIM1-Ca2+ Signaling Is Required for the Hypertrophic Growth of Skeletal Muscle in Mice.
T. Li, E. A. Finch, V. Graham, Z.-S. Zhang, J.-D. Ding, J. Burch, M. Oh-hora, and P. Rosenberg (2012)
Mol. Cell. Biol. 32, 3009-3017
   Abstract »    Full Text »    PDF »
Influence fields: a quantitative framework for representation and analysis of active dendrites.
R. K. Rathour and R. Narayanan (2012)
J Neurophysiol 107, 2313-2334
   Abstract »    Full Text »    PDF »
Urotensin-II Signaling Mechanism in Rat Coronary Artery: Role of STIM1 and Orai1-Dependent Store Operated Calcium Influx in Vasoconstriction.
A. Dominguez-Rodriguez, I. Diaz, M. Rodriguez-Moyano, E. Calderon-Sanchez, J. A. Rosado, A. Ordonez, and T. Smani (2012)
Arterioscler Thromb Vasc Biol 32, 1325-1332
   Abstract »    Full Text »    PDF »
Hypertrophy in Skeletal Myotubes Induced by Junctophilin-2 Mutant, Y141H, Involves an Increase in Store-operated Ca2+ Entry via Orai1.
J. S. Woo, C.-H. Cho, K. J. Lee, D. H. Kim, J. Ma, and E. H. Lee (2012)
J. Biol. Chem. 287, 14336-14348
   Abstract »    Full Text »    PDF »
Direct Binding Between Orai1 and AC8 Mediates Dynamic Interplay Between Ca2+ and cAMP Signaling.
D. Willoughby, K. L. Everett, M. L. Halls, J. Pacheco, P. Skroblin, L. Vaca, E. Klussmann, and D. M. F. Cooper (2012)
Science Signaling 5, ra29
   Abstract »    Full Text »    PDF »
STIM1 is required for attenuation of PMCA-mediated Ca2+ clearance during T-cell activation.
M. F. Ritchie, E. Samakai, and J. Soboloff (2012)
EMBO J. 31, 1123-1133
   Abstract »    Full Text »    PDF »
Activation of Intracellular Metabotropic Glutamate Receptor 5 in Striatal Neurons Leads to Up-regulation of Genes Associated with Sustained Synaptic Transmission Including Arc/Arg3.1 Protein.
V. Kumar, P. G. Fahey, Y.-J. I. Jong, N. Ramanan, and K. L. O'Malley (2012)
J. Biol. Chem. 287, 5412-5425
   Abstract »    Full Text »    PDF »
PDGF enhances store-operated Ca2+ entry by upregulating STIM1/Orai1 via activation of Akt/mTOR in human pulmonary arterial smooth muscle cells.
A. Ogawa, A. L. Firth, K. A. Smith, M. V. Maliakal, and J. X.- J. Yuan (2012)
Am J Physiol Cell Physiol 302, C405-C411
   Abstract »    Full Text »    PDF »
Hypoxia-induced Acidosis Uncouples the STIM-Orai Calcium Signaling Complex.
S. Mancarella, Y. Wang, X. Deng, G. Landesberg, R. Scalia, R. A. Panettieri, K. Mallilankaraman, X. D. Tang, M. Madesh, and D. L. Gill (2011)
J. Biol. Chem. 286, 44788-44798
   Abstract »    Full Text »    PDF »
Junctophilin 1 and 2 Proteins Interact with the L-type Ca2+ Channel Dihydropyridine Receptors (DHPRs) in Skeletal Muscle.
L. Golini, C. Chouabe, C. Berthier, V. Cusimano, M. Fornaro, R. Bonvallet, L. Formoso, E. Giacomello, V. Jacquemond, and V. Sorrentino (2011)
J. Biol. Chem. 286, 43717-43725
   Abstract »    Full Text »    PDF »
Human Regulatory T Cells Rapidly Suppress T Cell Receptor-Induced Ca2+, NF-{kappa}B, and NFAT Signaling in Conventional T Cells.
A. Schmidt, N. Oberle, E.-M. Weiss, D. Vobis, S. Frischbutter, R. Baumgrass, C. S. Falk, M. Haag, B. Brugger, H. Lin, et al. (2011)
Science Signaling 4, ra90
   Abstract »    Full Text »    PDF »
Relationship between Ca2+ sparklets and sarcoplasmic reticulum Ca2+ load and release in rat cerebral arterial smooth muscle.
Y. Takeda, M. A. Nystoriak, M. Nieves-Cintron, L. F. Santana, and M. F. Navedo (2011)
Am J Physiol Heart Circ Physiol 301, H2285-H2294
   Abstract »    Full Text »    PDF »
Store-Operated Calcium Channels: New Perspectives on Mechanism and Function.
R. S. Lewis (2011)
Cold Spring Harb Perspect Biol 3, a003970
   Abstract »    Full Text »    PDF »
Protein Kinase D3 Is a Pivotal Activator of Pathological Cardiac Hypertrophy by Selectively Increasing the Expression of Hypertrophic Transcription Factors.
C. Li, J. Li, X. Cai, H. Sun, J. Jiao, T. Bai, X. W. Zhou, X. Chen, D. L. Gill, and X. D. Tang (2011)
J. Biol. Chem. 286, 40782-40791
   Abstract »    Full Text »    PDF »
Splice Variant Specific Modulation of CaV1.2 Calcium Channel by Galectin-1 Regulates Arterial Constriction.
J. Wang, S. S. C. Thio, S. S. H. Yang, D. Yu, C. Y. Yu, Y. P. Wong, P. Liao, S. Li, and T. W. Soong (2011)
Circ. Res. 109, 1250-1258
   Abstract »    Full Text »    PDF »
Ion channels and transporters in cancer. 4. Remodeling of Ca2+ signaling in tumorigenesis: role of Ca2+ transport.
J. M. Lee, F. M. Davis, S. J. Roberts-Thomson, and G. R. Monteith (2011)
Am J Physiol Cell Physiol 301, C969-C976
   Abstract »    Full Text »    PDF »
Protein Folding and Quality Control in the ER.
K. Araki and K. Nagata (2011)
Cold Spring Harb Perspect Biol 3, a007526
   Abstract »    Full Text »    PDF »
Arterial Calcification in Chronic Kidney Disease: Key Roles for Calcium and Phosphate.
C. M. Shanahan, M. H. Crouthamel, A. Kapustin, and C. M. Giachelli (2011)
Circ. Res. 109, 697-711
   Abstract »    Full Text »    PDF »
Calcium Signaling in Smooth Muscle.
D. C. Hill-Eubanks, M. E. Werner, T. J. Heppner, and M. T. Nelson (2011)
Cold Spring Harb Perspect Biol 3, a004549
   Abstract »    Full Text »    PDF »
Orai1-Mediated ICRAC Is Essential for Neointima Formation After Vascular Injury.
W. Zhang, K. E. Halligan, X. Zhang, J. M. Bisaillon, J. C. Gonzalez-Cobos, R. K. Motiani, G. Hu, P. A. Vincent, J. Zhou, M. Barroso, et al. (2011)
Circ. Res. 109, 534-542
   Abstract »    Full Text »    PDF »
Socking It to Cardiac Hypertrophy: STIM1-Mediated Ca2+ Entry in the Cardiomyocyte.
P. Rosenberg (2011)
Circulation 124, 766-768
   Full Text »    PDF »
Critical Role for Stromal Interaction Molecule 1 in Cardiac Hypertrophy.
J.-S. Hulot, J. Fauconnier, D. Ramanujam, A. Chaanine, F. Aubart, Y. Sassi, S. Merkle, O. Cazorla, A. Ouille, M. Dupuis, et al. (2011)
Circulation 124, 796-805
   Abstract »    Full Text »    PDF »
TRPC1, STIM1, and ORAI Influence Signal-Regulated Intracellular and Endoplasmic Reticulum Calcium Dynamics in Human Myometrial Cells.
D. A. Murtazina, D. Chung, A. Ulloa, E. Bryan, H. L. Galan, and B. M. Sanborn (2011)
Biol Reprod 85, 315-326
   Abstract »    Full Text »    PDF »
Store-Operated Ca2+ Entry in Sensory Neurons: Functional Role and the Effect of Painful Nerve Injury.
G. Gemes, M. L. Y. Bangaru, H.-E. Wu, Q. Tang, D. Weihrauch, A. S. Koopmeiners, J. M. Cruikshank, W.-M. Kwok, and Q. H. Hogan (2011)
J. Neurosci. 31, 3536-3549
   Abstract »    Full Text »    PDF »
How to STIMulate Calcium Channels.
M. D. Cahalan (2010)
Science 330, 43-44
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882