E3 ubiquitin ligase rififylin has yin and yang effects on rabbit cardiac transient outward potassium currents (Ito) and corresponding channel proteins.

Genome-wide association studies have reported a correlation between a SNP of the RING finger E3 ubiquitin protein ligase rififylin (RFFL) and QT interval variability in humans (Newton-Cheh et al., 2009). Previously, we have shown that RFFL downregulates expression and function of the human-like ether-a-go-go-related gene potassium channel and corresponding rapidly activating delayed rectifier potassium current (IKr) in adult rabbit ventricular cardiomyocytes. Here, we report that RFFL also affects the transient outward current (Ito), but in a peculiar way. RFFL overexpression in adult rabbit ventricular cardiomyocytes significantly decreases the contribution of its fast component (Ito,f) from 35% to 21% and increases the contribution of its slow component (Ito,s) from 65% to 79%. Since Ito,f in rabbits is mainly conducted by Kv4.3, we investigated the effect of RFFL on Kv4.3 expressed in HEK293A cells. We found that RFFL overexpression reduced Kv4.3 expression and corresponding Ito,f in a RING domain-dependent manner in the presence or absence of its accessory subunit Kv channel-interacting protein 2. On the other hand, RFFL overexpression in Kv1.4-expressing HEK cells leads to an increase in both Kv1.4 expression level and Ito,s, similarly in a RING domain-dependent manner. Our physiologically detailed rabbit ventricular myocyte computational model shows that these yin and yang effects of RFFL overexpression on Ito,f, and Ito,s affect phase 1 of the action potential waveform and slightly decrease its duration in addition to suppressing IKr. Thus, RFFL modifies cardiac repolarization reserve via ubiquitination of multiple proteins that differently affect various potassium channels and cardiac action potential duration.

Identification of Transformation Products of Organic UV Filters by Photooxidation and Their Differential Estrogenicity Assessment.

Organic ultraviolet filters (OUVFs) are extensively released into aquatic environments, where they undergo complex phototransformation. However, there is little knowledge regarding their transformation products (TPs) and associated endocrine disruption potentials. In the present study, we characterized the chemical and toxicological profiles of TPs for two common OUVFs, oxybenzone (BP3) and ethylhexyl methoxycinnamate (EHMC), by photooxidation under environmentally relevant conditions. It is hypothesized that TPs of the tested OUVFs will show varied estrogenicity at different reaction times. High-resolution liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) identified 17 TPs of 7 m/z for BP-3 and 13 TPs of 8 m/z for EHMC at confidence levels ≤2. Five novel TPs of 2 m/z were reported for the first time with structure-diagnostic MS/MS spectra. Estrogenicity assessment using the MCF-7-luc cell line showed discrepant estrogenic activities exhibited by OUVF-TPs over time. Specifically, BP3-TPs exhibited significantly greater estrogenicity than the parent at several reaction times, whereas EHMC-TPs displayed fluctuating estrogenicity with a declining trend. Correlation analysis coupled with molecular docking simulations further suggested several TPs of BP3 as potential endocrine disruptive compounds. These findings underscore the necessity of considering mixtures during chemical testing and risk assessment and highlight the potentially greater risks associated with post-transformation cocktails.

The interactive effects of traffic sound and window views on indoor soundscape perceptions in the residential area.

Environmental noise has long been considered one of the unwelcome aspects of urban life at home. An increasing number of scholars have studied improving indoor acoustic comfort by using the soundscape approach. However, much uncertainty still exists about the relationship between the audio-visual environment and indoor soundscape perception. The current study investigates the interaction effects of traffic sound and window views on indoor soundscape perceptions in residential contexts. Thirty-two participants were presented with 51 scenarios (a combination of 17 window views and three aural stimuli) and requested to assess their soundscape perceptions in a VR experiment. Results showed that traffic noise could moderate the impact of nature, road, and building views on pleasantness, while it can also moderate the effect of water sound and road view on eventfulness. In particular, natural window views were found not to lead to a more pleasant indoor soundscape necessarily; natural window views even decrease the pleasantness of indoor soundscape in the case of heavy traffic noise outside the window. Besides, overall visual indicators, including complexity and openness, have an interactive effect with traffic sound on pleasantness. Last, pleasantness is found to be associated with the appropriateness of indoor soundscape.

Electrolyte and Interphase Design for Magnesium Anode: Major Challenges and Perspectives.

The rechargeable magnesium battery (RMB) is regarded as a high-energy, safe, and cost-effective alternative for conventional batteries. Unfortunately, the passivation and uneven Mg growth not only raise the voltage hysteresis but also shorten the cycle life of RMBs. In this review, Mg passivation induced by electrolytes/contaminants, growth patterns of high dimensional Mg0 , and mechanisms of Mg anode degradation are discussed. The recent efforts on suppressing electrolyte decomposition and uneven Mg growth including electrolyte/interphase modifications through additives, weakly coordinating anions, artificial interphases, and 3D magnesiophilic hosts are summarized. Finally, the future directions in stabilizing Mg anode and realizing high-performance RMBs are highlighted.

The antiestrogen-like activity and reproductive toxicity of 2,6-DCBQ on female zebrafish upon sub-chronic exposure.

2,6-Dichloro-1,4-benzoquinone (2,6-DCBQ), an emerging water disinfection by-product, is widely detected in water resources. However, its potential effects on the reproductive system are largely unknown. Here, we investigated the long-term effects of 2,6-DCBQ on gonadal development by exposing zebrafish from 15 to 180 days postfertilization (dpf). Following exposure to 2,6-DCBQ (20 and 100 µg/L), female-specific effects including delayed puberty onset, retarded ovarian growth and breakdown of the zona radiata were observed, resulting in subfertility in adult females. Adverse effects in folliculogenesis disappeared two months after cessation of 2,6-DCBQ administration. In contrast, no adverse impacts were noted in male testes. The effects on females were associated with significant reduction in 17ß-estradiol (E2) level, suggesting a role for 2,6-DCBQ in anti-estrogenic activity. E2 level change in blood was further supported by dysregulated expression of genes (cyp19a1a, fshb, kiss3, esr2b, vtg1, and vtg3) related to the hypothalamic-pituitary-gonad-liver (HPGL) axis. The present study demonstrates for the first time that 2,6-DCBQ induces reproductive impairments in female zebrafish through disrupting 17ß-estradiol level.

The endosomal trafficking regulator LITAF controls the cardiac Nav1.5 channel via the ubiquitin ligase NEDD4-2.

The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor-α factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current INa and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed in HEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression down-regulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressed NEDD4-2 and significantly blunted the negative effect of NEDD4-2 on INa We conclude that LITAF controls cardiac excitability by promoting degradation of NEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca2+ and Na+ homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation.

Molecular crowding electrolytes for high-voltage aqueous batteries.

Developing low-cost and eco-friendly aqueous electrolytes with a wide voltage window is critical to achieve safe, high-energy and sustainable Li-ion batteries. Emerging approaches using highly concentrated salts (21-55 m (mol kg-1)) create artificial solid-electrode interfaces and improve water stability; however, these approaches raise concerns about cost and toxicity. Molecular crowding is a common phenomenon in living cells where water activity is substantially suppressed by molecular crowding agents through altering the hydrogen-bonding structure. Here we demonstrate a 'molecular crowding' electrolyte using the water-miscible polymer poly(ethylene glycol) as the crowding agent to decrease water activity, thereby achieving a wide electrolyte operation window (3.2 V) with low salt concentration (2 m). Aqueous Li4Ti5O12/LiMn2O4 full cells with stable specific energies between 75 and 110 W h kg-1 were demonstrated over 300 cycles. Online electrochemical mass spectroscopy revealed that common side reactions in aqueous Li-ion batteries (hydrogen/oxygen evolution reactions) are virtually eliminated. This work provides a path for designing high-voltage aqueous electrolytes for low-cost and sustainable energy storage.

Trafficking of the human ether-a-go-go-related gene (hERG) potassium channel is regulated by the ubiquitin ligase rififylin (RFFL).

The QT interval is an important diagnostic feature on surface electrocardiograms because it reflects the duration of the ventricular action potential. A previous genome-wide association study has reported a significant linkage between a single-nucleotide polymorphism ∼11.7 kb downstream of the gene encoding the RING finger ubiquitin ligase rififylin (RFFL) and variability in the QT interval. This, along with results in animal studies, suggests that RFFL may have effects on cardiac repolarization. Here, we sought to determine the role of RFFL in cardiac electrophysiology. Adult rabbit cardiomyocytes with adenovirus-expressed RFFL exhibited reduced rapid delayed rectifier current (IKr). Neonatal rabbit cardiomyocytes transduced with RFFL-expressing adenovirus exhibited reduced total expression of the potassium channel ether-a-go-go-related gene (rbERG). Using transfections of 293A cells and Western blotting experiments, we observed that RFFL and the core-glycosylated form of the human ether-a-go-go-related gene (hERG) potassium channel interact. Furthermore, RFFL overexpression led to increased polyubiquitination and proteasomal degradation of hERG protein and to an almost complete disappearance of IKr, which depended on the intact RING domain of RFFL. Blocking the ER-associated degradation (ERAD) pathway with a dominant-negative form of the ERAD core component, valosin-containing protein (VCP), in 293A cells partially abolished RFFL-mediated hERG degradation. We further substantiated the link between RFFL and ERAD by showing an interaction between RFFL and VCP in vitro We conclude that RFFL is an important regulator of voltage-gated hERG potassium channel activity and therefore cardiac repolarization and that this ubiquitination-mediated regulation requires parts of the ERAD pathway.

A high-rate and long-life organic-oxygen battery.

Alkali metal-oxygen batteries promise high gravimetric energy densities but suffer from low rate capability, poor cycle life and safety hazards associated with metal anodes. Here we describe a safe, high-rate and long-life oxygen battery that exploits a potassium biphenyl complex anode and a dimethylsulfoxide-mediated potassium superoxide cathode. The proposed potassium biphenyl complex-oxygen battery exhibits an unprecedented cycle life (3,000 cycles) with a superior average coulombic efficiency of more than 99.84% at a high current density of 4.0 mA cm-2. We further reduce the redox potential of biphenyl by adding the electron-donating methyl group to the benzene ring, which successfully achieved a redox potential of 0.14 V versus K/K+. This demonstrates the direction and opportunities to further improve the cell voltage and energy density of the alkali-metal organic-oxygen batteries.

Reverse Electrodialysis Chemical Cell for Energy Harvesting from Controlled Acid-Base Neutralization.

We report a novel reverse electrodialysis (RED) chemical cell that integrates RED with acid/base neutralization. This RED neutralization process (REDn) approximately doubled the power density compared to a conventional RED stack (REDc), thanks to the additional salinity gradients established by H+ and OH- ions as a result of the neutralization reaction. Detailed analysis shows that the power performance, i.e., the open circuit voltage and power density, of the REDn cell was greatly limited by concentration polarization and uphill transport of ions. Addressing these issues could potentially lead to an order of magnitude improvement in power density as predicted by the Nernst equation. The current study provides a simple strategy for effectively extracting energy from the neutralization of waste acid and base solutions. Future studies shall further explore the treatment of acid mine drainage and landfill leachate with the RED chemical cell as well as its extension to a wider range of reactions.

Isotopic Labeling Reveals Active Reaction Interfaces for Electrochemical Oxidation of Lithium Peroxide.

The unresolved debate on the active reaction interface of electrochemical oxidation of lithium peroxide (Li2 O2 ) prevents rational electrode and catalyst design for lithium-oxygen (Li-O2 ) batteries. The reaction interface is studied by using isotope-labeling techniques combined with time-of-flight secondary ion mass spectrometry (ToF-SIMS) and on-line electrochemical mass spectroscopy (OEMS) under practical cell operation conditions. Isotopically labelled microsized Li2 O2 particles with an Li2 16 O2 /electrode interface and an Li2 18 O2 /electrolyte interface were fabricated. Upon oxidation, 18 O2 was evolved for the first quarter of the charge capacity followed by 16 O2 . These observations unambiguously demonstrate that oxygen loss starts from the Li2 O2 /electrolyte interface instead of the Li2 O2 /electrode interface. The Li2 O2 particles are in continuous contact with the catalyst/electrode, explaining why the solid catalyst is effective in oxidizing solid Li2 O2 without losing contact.

Cation-Directed Selective Polysulfide Stabilization in Alkali Metal-Sulfur Batteries.

Alkali metal sulfur redox chemistry offers promising potential for high-energy-density energy storage. Fundamental understanding of alkali metal sulfur redox reactions is the prerequisite for rational designs of electrode and electrolyte. Here, we revealed a strong impact of alkali metal cation (Li+, Na+, K+, and Rb+) on polysulfide (PS) stability, redox reversibility, and solid product passivation. We employed operando UV-vis spectroscopy to show that strongly negatively charged short-chain PS (e.g., S42-/S32-) is more stabilized in the electrolyte with larger cation (e.g., Rb+) than that with the smaller cation (e.g., Li+), which is attributed to a stronger cation-anion electrostatic interaction between Rb+ and S42-/S32- owing to its weaker solvation energy. In contrast, Li+ is much more strongly solvated by solvent and thus exhibits a weaker electrostatic interaction with S42-/S32-. The stabilization of short-chain PS in K+-, Rb+-sulfur cells promotes the reduction of long-chain PS to short-chain PS, leading to high discharge potential. However, it discourages the oxidation of short-chain PS to long-chain PS, leading to poor charge reversibility. Our work directly probes alkali metal-sulfur redox chemistry in operando and provides critical insights into alkali metal sulfur reaction mechanism.

Non-covalent interactions in electrochemical reactions and implications in clean energy applications.

Understanding and controlling non-covalent interactions associated with solvent molecules and redox-inactive ions provide new opportunities to enhance the reaction entropy changes and reaction kinetics of metal redox centers, which can increase the thermodynamic efficiency of energy conversion and storage devices. Here, we report systematic changes in the redox entropy of one-electron transfer reactions including [Fe(CN)6]3-/4-, [Fe(H2O)6]3+/2+ and [Ag(H2O)4]+/0 induced by the addition of redox inactive ions, where approximately twenty different known structure making/breaking ions were employed. The measured reaction entropy changes of these redox couples were found to increase linearly with higher concentration and greater structural entropy (having greater structure breaking tendency) for inactive ions with opposite charge to the redox centers. The trend could be attributed to the altered solvation shells of oxidized and reduced redox active species due to non-covalent interactions among redox centers, inactive ions and water molecules, which was supported by Raman spectroscopy. Not only were these non-covalent interactions shown to increase reaction entropy, but they were also found to systematically alter the redox kinetics, where increasing redox reaction energy changes associated with the presence of water structure breaking cations were correlated linearly with the greater exchange current density of [Fe(CN)6]3-/4-.

Superoxide Stabilization and a Universal KO2 Growth Mechanism in Potassium-Oxygen Batteries.

Rechargeable potassium-oxygen (K-O2 ) batteries promise to provide higher round-trip efficiency and cycle life than other alkali-oxygen batteries with satisfactory gravimetric energy density (935 Wh kg-1 ). Exploiting a strong electron-donating solvent, for example, dimethyl sulfoxide (DMSO) strongly stabilizes the discharge product (KO2 ), resulting in significant improvement in electrode kinetics and chemical/electrochemical reversibility. The first DMSO-based K-O2 battery demonstrates a much higher energy efficiency and stability than the glyme-based electrolyte. A universal KO2 growth model is developed and it is demonstrated that the ideal solvent for K-O2 batteries should strongly stabilize superoxide (strong donor ability) to obtain high electrode kinetics and reversibility while providing fast oxygen diffusion to achieve high discharge capacity. This work elucidates key electrolyte properties that control the efficiency and reversibility of K-O2 batteries.

Critical Role of Redox Mediator in Suppressing Charging Instabilities of Lithium-Oxygen Batteries.

Redox mediators have been widely applied to reduce the charge overpotentials of lithium-oxygen (Li-O2) batteries. Here, we reveal the critical role of redox mediator in suppressing the charging instability of Li-O2 batteries. Using high temporal resolution online electrochemical mass spectrometry, we show that charging with redox mediators (using lithium bromide as a model system) significantly reduces parasitic gas evolution and improves oxygen recovery efficiency. Using redox mediator transforms the charge reactions from electrochemical pathways to chemical pathways, which unexpectedly bypasses the formation of highly reactive intermediates upon electro-oxidation of lithium peroxide (Li2O2). Such transformation reduces self-amplifying degradation reactions of electrode and electrolyte in Li-O2 cells. We further show that the improved stability associated with the redox mediator is much more pronounced at higher charging rates, owing to fast charge-transfer kinetics of the redox mediator. Together, we show that employing redox mediator not only reduces the charge overpotential but also suppresses side reactions of Li-O2 cells with improved charging rate. Our work demonstrates that transforming electro-oxidation of Li2O2 to chemical oxidation of Li2O2 is a promising strategy to simultaneously mitigate charging side reactions and achieve low overpotential for the Li-O2 batteries.

Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of inherited neuropathies. Mutations in approximately 45 genes have been identified as being associated with CMT. Nevertheless, the genetic etiologies of at least 30% of CMTs have yet to be elucidated. Using a genome-wide linkage study, we previously mapped a dominant intermediate CMT to chromosomal region 3q28-q29. Subsequent exome sequencing of two affected first cousins revealed heterozygous mutation c.158G>A (p.Gly53Asp) in GNB4, encoding guanine-nucleotide-binding protein subunit beta-4 (Gß4), to cosegregate with the CMT phenotype in the family. Further analysis of GNB4 in an additional 88 unrelated CMT individuals uncovered another de novo mutation, c.265A>G (p.Lys89Glu), in this gene in one individual. Immunohistochemistry studies revealed that Gß4 was abundant in the axons and Schwann cells of peripheral nerves and that expression of Gß4 was significantly reduced in the sural nerve of the two individuals carrying the c.158G>A (p.Gly53Asp) mutation. In vitro studies demonstrated that both the p.Gly53Asp and p.Lys89Glu altered proteins impaired bradykinin-induced G-protein-coupled-receptor (GPCR) signaling, which was facilitated by the wild-type Gß4. This study identifies GNB4 mutations as a cause of CMT and highlights the importance of Gß4-related GPCR signaling in peripheral-nerve function in humans.

Hyperphosphorylation of RyRs underlies triggered activity in transgenic rabbit model of LQT2 syndrome.

RATIONALE: Loss-of-function mutations in human ether go-go (HERG) potassium channels underlie long QT syndrome type 2 (LQT2) and are associated with fatal ventricular tachyarrhythmia. Previously, most studies focused on plasma membrane-related pathways involved in arrhythmogenesis in long QT syndrome, whereas proarrhythmic changes in intracellular Ca(2+) handling remained unexplored. OBJECTIVE: We investigated the remodeling of Ca(2+) homeostasis in ventricular cardiomyocytes derived from transgenic rabbit model of LQT2 to determine whether these changes contribute to triggered activity in the form of early after depolarizations (EADs). METHODS AND RESULTS: Confocal Ca(2+) imaging revealed decrease in amplitude of Ca(2+) transients and sarcoplasmic reticulum Ca(2+) content in LQT2 myocytes. Experiments using sarcoplasmic reticulum-entrapped Ca(2+) indicator demonstrated enhanced ryanodine receptor (RyR)-mediated sarcoplasmic reticulum Ca(2+) leak in LQT2 cells. Western blot analyses showed increased phosphorylation of RyR in LQT2 myocytes versus controls. Coimmunoprecipitation experiments demonstrated loss of protein phosphatases type 1 and type 2 from the RyR complex. Stimulation of LQT2 cells with ß-adrenergic agonist isoproterenol resulted in prolongation of the plateau of action potentials accompanied by aberrant Ca(2+) releases and EADs, which were abolished by inhibition of Ca(2+)/calmodulin-dependent protein kinase type 2. Computer simulations showed that late aberrant Ca(2+) releases caused by RyR hyperactivity promote EADs and underlie the enhanced triggered activity through increased forward mode of Na(+)/Ca(2+) exchanger type 1. CONCLUSIONS: Hyperactive, hyperphosphorylated RyRs because of reduced local phosphatase activity enhance triggered activity in LQT2 syndrome. EADs are promoted by aberrant RyR-mediated Ca(2+) releases that are present despite a reduction of sarcoplasmic reticulum content. Those releases increase forward mode Na(+)/Ca(2+) exchanger type 1, thereby slowing repolarization and enabling L-type Ca(2+) current reactivation.

RING finger protein RNF207, a novel regulator of cardiac excitation.

Two recent studies (Newton-Cheh, C. et al. (2009) Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat. Genet. 41, 399-406 and Pfeufer, A. et al. (2009) Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat. Genet. 41, 407-414) identified an association, with genome-wide significance, between a single nucleotide polymorphism within the gene encoding RING finger protein 207 (RNF207) and the QT interval. We sought to determine the role of RNF207 in cardiac electrophysiology. Morpholino knockdown of RNF207 in zebrafish embryos resulted in action potential duration prolongation, occasionally a 2:1 atrioventricular block, and slowing of conduction velocity. Conversely, neonatal rabbit cardiomyocytes infected with RNF207-expressing adenovirus exhibited shortened action potential duration. Using transfections of U-2 OS and HEK293 cells, Western blot analysis and immunocytochemistry data demonstrate that RNF207 and the human ether-a-go-go-related gene (HERG) potassium channel interact and colocalize. Furthermore, RNF207 overexpression significantly elevated total and membrane HERG protein and HERG-encoded current density by ∼30-50%, which was dependent on the intact N-terminal RING domain of RNF207. Finally, coexpression of RNF207 and HSP70 increased HERG expression compared with HSP70 alone. This effect was dependent on the C terminus of RNF207. Taken together, the evidence is strong that RNF207 is an important regulator of action potential duration, likely via effects on HERG trafficking and localization in a heat shock protein-dependent manner.

Progesterone modulates SERCA2a expression and function in rabbit cardiomyocytes.

We recently showed that progesterone treatment abolished arrhythmias and sudden cardiac death in a transgenic rabbit model of long QT syndrome type 2 (LQT2). Moreover, levels of cardiac sarco(endo)plasmic reticulum Ca(2+)-ATPase type 2a (SERCA2a) were upregulated in LQT2 heart extracts. We hypothesized that progesterone treatment upregulated SERCA2a expression, thereby reducing Ca(2+)-dependent arrhythmias in LQT2 rabbits. We therefore investigated the effect of progesterone on SERCA2a regulation in isolated cardiomyocytes. Cardiomyocytes from neonatal (3- to 5-day-old) rabbits were isolated, cultured, and treated with progesterone and other pharmacological agents. Immunoblotting was performed on total cell lysates and sarcoplasmic reticulum-enriched membrane fractions for protein abundance, and mRNA transcripts were quantified using real-time PCR. The effect of progesterone on baseline Ca(2+) transients and Ca(2+) clearance was determined using digital imaging. Progesterone treatment increased the total pool of SERCA2a protein by slowing its degradation. Using various pharmacological inhibitors of degradation pathways, we showed that progesterone-associated degradation of SERCA2a involves ubiquitination, and progesterone significantly decreases the levels of ubiquitin-tagged SERCA2a polypeptides. Our digital imaging data revealed that progesterone significantly shortened the decay and duration of Ca(2+) transients. Progesterone treatment increases protein levels and activity of SERCA2a. Progesterone stabilizes SERCA2a, in part, by decreasing the ubiquitination level of SERCA2a polypeptides.