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First published online 13 December 2005
doi: 10.1242/jcs.02731
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Research Article |
1 Department of Physiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
2 Skirball Institute of Biomolecular Medicine and the Departments of Cell Biology, Medicine and Pharmacology, New York University School of Medicine, 530 First Avenue, New York, NY 10016, USA
Author for correspondence (e-mail: shmuel.muallem{at}utsouthwestern.edu)
Accepted 4 October 2005
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Summary |
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to attenuate protein synthesis. PERK-/- cells are unable to modulate ER protein load and experience high levels of ER stress. In addition to its role in protein synthesis, the ER also orchestrates many signaling events essential for cell survival, prominent among which is Ca2+ signaling. It is not known, however, whether there is a relationship between ER stress and the function of the Ca2+-signaling pathway in muscle and non-muscle cells. To directly address this question we characterized Ca2+ signaling in the secretory pancreatic and parotid acinar cells and in urinary bladder smooth muscle (UBSM) cells obtained from PERK-/- and wild-type mice. Deletion of PERK that results in high levels of ER stress, and distention and fragmentation of the ER slowed the rate of agonist-mediated Ca2+ release from the ER and reduced Ca2+-induced Ca2+ release, although IP3 production, localization of the IP3 receptors, IP3-mediated Ca2+ release, Cav1.2 current and RyRs activity remained unaltered. On the other hand, ER stress disrupted the integrity of the Ca2+-signaling complexes in both secretory and UBSM cells, as revealed by markedly reduced co-immunoprecipitation of plasma membrane- and ER-resident Ca2+-signaling proteins. These findings establish a relationship between the unfolding protein response, ER stress and Ca2+ signaling and highlight the importance of communication within the terminal ER-plasma membrane microdomain for propagation of the Ca2+ signal from the plasma membrane into the cell.
Key words: ER stress, Ca2+-signaling complexes, Ca2+ regulation, PERK-/- cells, Unfolded protein response
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Introduction |
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; Sitia and Braakman, 2003). This is a challenging process, as client proteins that fail to attain their properly folded and assembled state threaten the integrity of the organelle by constituting an ER stress (Aridor and Balch, 1999). Complex cellular adaptations have evolved to combat this threat. These are triggered by the load of unfolded and misfolded client proteins and activate genes encoding components of the aforementioned ER machinery, increasing its capacity to handle client protein load and alleviate the stress (Kaufman, 2002; Patil and Walter, 2001). Protein synthesis is also modulated by ER stress to mitigate the load of newly synthesized, unfolded, client proteins imposed on the organelle (Ron, 2002). The signal transduction pathways that collectively effect these adaptations are said to constitute an unfolded protein response (UPR) to ER stress.
Mounting evidence suggests that ER stress plays a role in the pathophysiology of diverse diseases affecting secretory cells. For example, dominant cis-acting mutations that impede folding of abundantly expressed ER client proteins such as insulin (Oyadomari et al., 2002b; Wang et al., 1999), collagen (Lamande and Bateman, 1999), and myelin components (Gow et al., 1998) affect the function of the endocrine pancreas, bone and nervous tissue by mechanisms that probably include toxic, gain-of-function features of the misfolded protein. Furthermore, mutations in components of the UPR preferentially affect secretory cells. This is dramatically revealed by mutations in pancreatic ER kinase (PERK), a ubiquitously-expressed ER localized protein kinase that phosphorylates the alpha subunit of translation initiation factor 2 (eIF2a) to attenuate protein synthesis in ER-stressed cells (Harding et al., 1999; Sood et al., 2000). PERK-knockout cells are unable to modulate ER client protein load and experience abnormally high levels of ER stress imposed by their physiological secretory products (Harding et al., 2000b). The prominent phenotype of mice and humans lacking PERK is focused in secretory cells, exocrine and endocrine pancreatic insufficiency, liver dysfunction and osteoblast failure (Delepine et al., 2000; Harding et al., 2001; Zhang et al., 2002).
Most studies of the pathophysiology of ER stress have emphasized the potential role of cell death in organ dysfunction (Harding et al., 2001; Oyadomari et al., 2002a; Southwood et al., 2002). Indeed, the conditions mentioned above are associated with markedly accelerated rates of secretory cell death. It is unclear however, if ER stress also contributes to declining organ activity by promoting secretory cell dysfunction. In addition to its role in the biosynthesis of secretory proteins, the ER also orchestrates many of the signaling events that regulate secretion, as described below. It is conceivable, therefore, that stress imposed by unfolded client proteins might also affect this regulatory function of the organelle. Furthermore, prominent morphological abnormalities have been observed in the ER of secretory cells expressing mutant client proteins or lacking PERK activity (Harding et al., 2001; Wang et al., 1999; Zhang et al., 2002) and these might constitute the anatomical substrate of such a functional defect.
The signals triggering regulated secretion are initiated at the plasma membrane by stimulation of G-protein-coupled receptors (GPCRs) to evoke changes in free cytosolic Ca2+ concentration ([Ca2+]i) that are translated into the secretory response (Bi and Williams, 2004; Kiselyov et al., 2003). Ca2+ signaling by GPCRs involves assembly of Ca2+ signaling proteins into complexes in cellular microdomains to generate receptor and cell specific Ca2+ signals (Kiselyov et al., 2003; Petersen, 2002). Several constituents of the Ca2+-signaling complex are present in all GPCR complexes. The plasma membrane (PM)-resident module includes the receptor, the heterotrimeric G protein Gq and phospholipase C ß (PLCß). This biochemical module generates IP3 to activate the IP3Rs and release Ca2+ stored in the ER. The PM module also includes the store-operated Ca2+ influx channel(s) (SOCs) and the PM Ca2+ pump (PMCA). The ER module of the Ca2+-signaling complex includes the IP3 receptors and the sarco/endoplasmic reticulum Ca2+ pump (SERCA) (Berridge et al., 2000; Kiselyov et al., 2003). In specialized cells, such as salivary gland cells (Lee et al., 1997; Yao et al., 2004) and urinary bladder smooth muscle (UBSM) cells (Wegener et al., 2004) the dominant Ca2+-release channels in the ER are the ryanodine receptors (RyRs) that are activated by a Ca2+-induced Ca2+ release (CICR) mechanism. In UBSM cells Ca2+ influx across the PM is predominantly mediated by the L type Ca2+-channel isoform Cav1.2 (Wegener et al., 2004). Depletion of ER Ca2+ triggers ER stress and activates PERK (Harding et al., 1999), which is also observed in cells responding to physiological secretory agonists (Alcazar et al., 1997; Kimball and Jefferson, 1990; Kimball and Jefferson, 1991). Secretory cells that continually synthesise and secrete proteins, like pancreatic and parotid acinar cells, and muscle cells that frequently release and reuptake Ca2+ into the SR/ER should be particularly sensitive to this physiological form of ER stress.
The PM and ER modules of the Ca2+-signaling complex communicate on several levels. IP3 is generated by hydrolysis of PIP2 at the PM to release Ca2+ from the ER. Ca2+ release from the ER activates Ca2+-influx channels at the PM. Ca2+ influx across the PM through SOCs or Cav1.2 activates CICR by RyRs in the ER (Berridge et al., 2000; Kiselyov et al., 2003). These forms of communication are mediated by interaction of Ca2+-signaling proteins in both membranes. For example, the IP3Rs interacts with transient receptor potential (TRPC) channels to control Ca2+ influx (Boulay et al., 1999; Kiselyov et al., 1998; Yuan et al., 2003). Scaffolding proteins like Homers can directly bind IP3Rs, RyRs and canonical TRPC channels (Xiao et al., 2000; Yuan et al., 2003) and to other scaffolds like PSD95 and Shank to assemble the complexes (Kim and Sheng, 2004) and probably facilitate communication between the PM and ER Ca2+-signaling proteins. Communication between the PM and ER modules implies specialized terminal ER that is in close proximity to the PM. Integrity of this ER/PM domain is likely to be crucial for generating Ca2+ signals with high fidelity, such as the Ca2+ waves that are evoked by GPCRs in polarized cells (Kiselyov et al., 2003). Of particular interest was the possibility that distention and/or fragmentation of the ER, observed in PERK-knockout pancreas might disrupt the communication between the PM and ER components of the Ca2+-signaling complex.
To determine if secretory organ dysfunction in PERK-knockout animals might also have a functional basis, we examined Ca2+ signaling in pancreatic and parotid acinar cells and in UBSM cells of wild-type and PERK-/- mice. Our findings establish a relationship between ER stress and defective Ca2+ signaling and highlight the importance of communication within the terminal ER-PM microdomain for propagation of the Ca2+ signal from the PM into the cell.
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Results |
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) allowed us to study the role of ER integrity in specialized forms of Ca2+ signaling, such as the polarized Ca2+ waves in secretory cells (Kiselyov et al., 2003) and the Ca2+ signal mediating excitation-contraction coupling (E-C coupling) in muscle cells (Wegener et al., 2004). Surprisingly, the general features of Ca2+ signaling stimulated by high agonist concentrations appeared undisturbed in PERK-/- cells. Deletion of PERK had no effect on resting [Ca2+]i in pancreatic acini that averaged 77±5 and 69±8 nM in wild-type (WT) and PERK-/- cells, or on the [Ca2+]i evoked by stimulation with 1 mM of the muscarinic agonist carbachol, which was increased to 515±39 and 509±43 nM in WT and PERK-/- cells, respectively (Fig. 1A,B). Even more surprising was the finding that reloading of the ER Ca2+ stores following their complete discharge with carbachol was also unaffected by fragmentation of the ER (Fig. 1C). Reloading was measured by inhibition of carbachol stimulation with atropine in Ca2+-containing medium and re-stimulation with cholecystokinin (CCK), as we described before (Muallem et al., 1986; Muallem et al., 1988). Not only could the ER be fully loaded with Ca2+, but fragmentation of the ER did not slow the rate of the reloading. Therefore, it seems that integrity of the ER is not obligatory for the process of reloading that includes Ca2+ influx across the plasma membrane and uptake into the ER.
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Production and action of IP3 are unaltered in PERK-/- cells
The results in Figs 1, 2, 3 indicate that the most prominent effect of ER fragmentation on the Ca2+ signal is a marked reduction in the rate of Ca2+ release observed at low stimulus intensity. All other parameters of the Ca2+ signal appeared unaltered. This raised the possibility that IP3 production, localization of IP3Rs or IP3-mediated Ca2+ release were altered as a consequence of fragmentation of the ER. However, agonist-stimulated IP3 production (Fig. 4A,B), the localization of IP3Rs (Fig. 4C), the IP3-mediated Ca2+ release and its dependence on IP3 concentration (Fig. 4D,E) were all found to be the same in WT and PERK-/- cells. This indicates that the lesion caused by fragmentation of the ER is in a step distal to IP3 production and proximal to IP3-mediated Ca2+ release. The possible step will be discussed below.
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Fragmentation of the ER decreases efficiency of CICR
The effect of ER distention and/or fragmentation on the rate of Ca2+ release raised the question of whether this was specific to IP3-mediated Ca2+ release or also affected Ca2+-induced Ca2+ release (CICR) in muscle and non-muscle cells. The bulk of agonist-evoked Ca2+ release in salivary gland cells is mediated by a CICR mechanism (Lee et al., 1997; Yao et al., 2004). We measured CICR in parotid acinar cells from WT and PERK-/- mice by treating the cells with 1 mM carbachol or 10 µM of the SERCA pump inhibitor cyclopiasonic acid (CPA) in Ca2+-free medium and then repeatedly exposing them to cycles of 7.5 and 0 mM Ca2+ (Fig. 5). In an earlier work (Yao et al., 2004) we showed that treatment with 10 µM CPA for 2 minutes releases only a small fraction of the intracellular Ca2+ pool, but is sufficient to activate Ca2+ influx that triggers the CICR mechanism. The first CICR event in response to 7.5 mM Ca2+o increased [Ca2+]i to a higher level in the WT compared with PERK-/- cells treated with carbachol (493±38 and 372±44, n=6) or CPA (403±37 and 312±35, n=5). Furthermore, after the first event of CICR more Ca2+ was retained in the ER of PERK-/- cells, as evident from the higher number of CICR events needed to deplete their intracellular Ca2+ store and the higher ratio of the second or third to the first Ca2+ peak (Fig. 5F). These findings indicate that fragmentation of the ER also disrupt CICR in non-muscle cells.
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). E-C coupling in this muscle involves activation of Cav1.2 by membrane depolarization and Ca2+ influx that activates RyR2 to induce a large CICR (Wegener et al., 2004). The effect of membrane depolarization on [Ca2+]i and contraction were measured by incubating the strips at increasing external K+ concentrations (Fig. 6). Deletion of PERK reduced the [Ca2+]i and the contractile response of the UBSM to intermediate membrane depolarization steps without affecting the maximal responses to strong depolarization with 80 mM external K+.
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), immunoprecipitation of PMCA co-immunoprecipitated the IP3R3 and SERCA2b in WT acini. Notably, the co-immunoprecipitation was nearly abolished in PERK-/- cells. Deletion of PERK slightly increased expression of Cav1.2 and RyR2 in UBSM, which may represent adaptation of the Ca2+-signaling complex to fragmentation of the ER (Fig. 8B). Significantly, immunoprecipitation of Cav1.2 co-immunoprecipitated RyR2 in WT UBSM, which was markedly reduced in PERK-/- UBSM. These findings indicate that deletion of PERK and fragmentation of the ER resulted in a general disruption of Ca2+-signaling complexes in the PM/ER microdomain, which can explain well the reduced rate and efficiency of Ca2+ release from internal stores. |
Discussion |
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When considering the mechanism(s) accounting for this functional defect in PERK-/- cells it is important to keep in mind that in addition to regulating protein synthesis and thereby ER client protein load, ER-stress-induced PERK signaling also activates an eIF2 phosphorylation-mediated gene expression program (Harding et al., 2000a; Scheuner et al., 2001). The targets of this gene expression program participate in many cellular processes, including amino acid metabolism, antioxidant responses and more conventional enhancement of the ER machinery (Harding et al., 2003). Our study does not discriminate between the impact of the PERK mutation on the levels of ER stress and its potential to promote a specific defect in expression of the gene(s) required for Ca2+ signaling.
Deranged Ca2+ signaling uncovered by our experiments suggests that in addition to their effect on secretory cell survival, PERK mutations are also associated with a functional defect affecting these cells. This defect probably contributes to the diabetic phenotype and malabsorption observed in affected individuals with rare mutations in PERK (the so-called Wolcott-Rallison syndrome) (Delepine et al., 2000). Of potentially greater clinical significance is the possibility that milder levels of ER stress are also associated with qualitatively similar functional defects in ER Ca2+ signaling. ER stress is a physiological phenomenon, whose intensity is likely to be modulated over the physiological range of client protein load. Thus, one might expect higher levels of ER stress in the insulin producing ß-cells of individuals with peripheral resistance to the hormone; a physiological stress imposed by the need to produce large quantities of this ER client protein. It is tempting to speculate that this chronic ER stress might contribute to a functional defect in regulated insulin secretion that eventually leads to overt diabetes mellitus in a subset of such individuals.
Our findings also call attention to an important role for PERK (and ER integrity) in E-C coupling in muscle cells. Though their role in protein secretion is relatively modest, it has recently been suggested that cardiomyocytes, like secretory cells, might also be susceptible to the adverse consequences of ER stress (Hamada et al., 2004). Other conditions, such as diabetic cardiomyopathy entail longer times for maximum cell shortening and relengthening, which is attributed to reduced expression and function of SERCA2a (Belke and Dillmann, 2004). Our findings suggest that ER stress in diabetes can further compromise cardiac function by disruption of E-C coupling. Hence, our study suggests a common pathophysiological mechanism by which chronic ER stress might perturb cardiac function by contributing to a defect in E-C coupling.
In summary, we have uncovered an intriguing defect in Ca2+ signaling in PERK-knockout cells. This defect helps to explain the decline in secretory cell function, which precedes the onset of massive secretory cell death. The molecular basis for this defect remains to be explored as does its pervasiveness in other conditions associated with chronic ER stress. The strengthening evidence for a link between ER stress and chronic diseases of aging, render this an important question for further study.
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Materials and Methods |
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Preparation of pancreatic and parotid acini
Acini were prepared as described (Lee et al., 1997). PERK-/- and WT offspring of PERK heterozygous matings (Harding et al., 2001) were anesthetized and killed by cervical dislocation. The pancreas and parotid glands were removed into PSA and digested with collagenase P at 37°C for 5-6 minutes. After digestion, the acini were washed with PSA and loaded with Fura2 by incubation for 30 minutes at 37°C with 10 µM Fura2/AM. The acini were washed once, suspended in PSA and kept on ice until use.
Preparation of urinary bladder smooth muscle cells and strips
For preparation of both UBSM cells and strips the bladder was excised into solution B and the urothelium was dissected away from the muscle. UBSM cells were prepared according to published methods (Ji et al., 2002) and in brief as follows. The muscle was minced and incubated for 20 minutes at 37°C in solution B supplemented with 1 mg/ml papain, 1 mg/ml dithioerythritol and 1 mg/ml BSA. The fragments were washed twice with solution B and transferred into solution B supplemented with 1 mg/ml collagenase type 2, 100 µM Ca2+ and 1 mg/ml BSA and incubated at 37°C for 10 minutes. The resulting digest was washed twice with solution B, triturated with a wide-bore Pasteur pipette, and passed through 125 µm nylon mesh. The cells were concentrated by low speed centrifugation (100 g), washed once with fresh solution B, resuspended and kept on ice until use for current measurements. UBSM strips were prepared as before (Isotani et al., 2004). The bladder was dissected into three strips of about 0.5x0.5x8.0 mm. The strips were stretched (x1.2 slack length), and incubated in the dark with solution B containing 10 µM Indo-1 AM or 10 µM Fura-2 AM, 0.01% pluronic F-127 and 0.02% cremophor for 4 hours at room temperature. After the incubation, the strips were washed with fresh solution B for 30 minutes at room temperature and used for simultaneous measurements of [Ca2+]i and contraction (Indo-1) or only [Ca2+]i (Fura2) in the case of stimulation with caffeine as caffeine interferes with Indo-1 fluorescence.
Measurement of Ca2+ in acini
Acini loaded with Fura2 were plated on poly-L-lysine-coated glass coverslips that formed the bottom of a perfusion chamber. The acini were perfused with a warm (37°C) solution A and agonists were delivered with the perfusate. Fura2 fluorescence was recorded using a PTI image equation and analysis system and the fluorescence signals were calibrated as detailed before (Shin et al., 2001). Ca2+ waves were recorded using a single excitation wavelength of 380 nm. The image of resting cells was acquired and taken as the fluorescence signal of time 0 (F0). All subsequent images were divided by F0, and the images or traces are presented as Ft/F0, where Ft is the fluorescence at time t.
Measurement of [Ca2+]i and contraction in smooth muscle strips
Simultaneous measurements of mechanical and optical parameters of muscle strips were made with a fluorescence myograph (Scientific Instruments, Heidelberg) as described (Isotani et al., 2004). Indo-1-loaded strips were mounted on a force transducer in a quartz cuvette and were illuminated at 365 nm. Emitted light was recorded at 405 nm and 485 nm to obtain the 405/485 ratio. The 405/485 emission ratios and isometric force were recorded simultaneously. Fura2-loaded UBSM strips were taped onto glass coverslips and fluorescence was measured by illumination at 350 and 380 nm and the emitted light was used to calculate the 350/380 ratio.
Measurement of Cav1.2 current in UBSM cells
Patch pipettes are filled with a solution containing 155 mM CsCl, 10 mM Cs4EGTA, 1 mM MgATP and 10 mM HEPES adjusted to pH 7.2 with CsOH. The bath solution contained 140 mM NaCl, 10 mM BaCl2, 4 mM KCl and 10 mM HEPES adjusted to pH 7.4 with NaOH. Filled pipettes had an average resistance of 2-4 M
. Ba2+ currents were recorded in the whole-cell mode. Data were sampled at 10 kHz and filtered at 1 kHz. During whole-cell recording I/V relations were obtained by holding the membrane potential at -80 mV and stepping at 10 mV intervals to +60 mV. The pCLAMP6 software programs Clampex and Clampfit were used for data acquisition and analysis, respectively. Figures were made using Origin version 7.5.
Mass measurement of IP3
Acini in solution A were stimulated with the indicated agonist concentration for 2-10 seconds. The reactions were stopped and the proteins precipitated by addition of perchloric acid to a final concentration of 5% and incubating the acini for at least 20 minutes on ice. IP3 was extracted with a mixture of 0.2 ml Freon and 0.2 ml tri-n-octylamine and IP3 was measured by a standard radioligand assay, as reported (Wang et al., 2004).
IP3-mediated Ca2+ release in SLO-permeabilized cells
To measure IP3-mediated Ca2+ release the cells were washed twice with a solution containing 145 mM KCl and 10 mM HEPES (pH 7.4), and once with the same solution treated with Chelex 100. The acini were transferred to a fluorimeter cuvette containing warm incubation medium composed of the Chelex-treated solution, an ATP-regenerating system composed of 3 mM ATP, 5 mM MgCl2, 10 mM creatine phosphate, 5 U/ml creatine kinase), a cocktail of mitochondrial inhibitors, 2 µM Fluo3 and 3 mg/ml streptolysine O (SLO). Ca2+ uptake into the ER was allowed to continue until [Ca2+] in the medium was stabilized. Then IP3 was added in increasing concentrations to measure the extent of Ca2+ release and the potency of IP3 in mobilizing Ca2+ from the ER.
Immunocytochemistry
Cells attached to glass coverslips were fixed and permeabilized with cold methanol for 10 minutes at -20°C. The cells were washed with PBS, PBS containing 50 mM glycine and the nonspecific sites were blocked by incubation for 1 hour with PBS containing 5% goat serum, 1% bovine serum albumin and 0.1% gelatin (blocking buffer). The medium was aspirated and replaced with 50 µl blocking buffer containing control serum or 1:100 dilution of anti-IP3R1, anti-IP3R2 or anti-IP3R3. After incubation with the primary antibodies overnight at 4°C and three washes with the blocking buffer, the antibodies were detected with goat anti-rabbit IgG tagged with Fluorescein or Rhodamine. Images were collected with a Bio-Rad MRC 1024 confocal microscope.
Immunoprecipitation and western blot analysis
Microsomes were prepared by homogenizing the pancreas, heart or urinary bladder in a buffer containing 250 mM sucrose, 10 mM HEPES (pH 7.4), 1 mM EDTA, 1 mM DTT and 0.2 mM PMSF. The homogenates were centrifuged at 1000 g for 10 minutes at 4°C. The supernatants were collected and centrifuged at 40,000 g for 20 minutes. The pellets were resuspended in lysis buffer composed of 50 mM Tris-HCl (pH 6.8), 150 mM NaCl, 2 mM EDTA, 2 mM EGTA and 1% Triton X-100 supplemented with protease inhibitors (0.2 PMSF, 10 µg/µl leupeptin, 15 µg/µl aprotinin, 1 mM benzamidine) and extracted by incubation for 1 hour on ice. The lysate was centrifuged to remove insoluble material and the extracts were used for co-immunoprecipitation by incubation with anti-PMCA of anti-Cav1.2 overnight at 4°C. The complexes were captured by addition of 50 µl of 1:1 protein G Sepharose slurry and incubation for 3 hours at 4°C. After washing, the proteins were eluted from the beads by incubation with 40 µl SDS loading buffer for 45 minutes at 70°C and 20 µl samples were analyzed by SDS-PAGE. Proteins were detected by incubation of individual membranes for 2 hours with the respective antibody diluted in 5% non-fat milk.
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Footnotes |
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  G. Huang, J. Y. Kim, M. Dehoff, Y. Mizuno, K. E. Kamm, P. F. Worley, S. Muallem, and W. Zeng Ca2+ Signaling in Microdomains: Homer1 MEDIATES THE INTERACTION BETWEEN RyR2 AND Cav1.2 TO REGULATE EXCITATION-CONTRACTION COUPLING J. Biol. Chem., May 11, 2007; 282(19): 14283 - 14290. [Abstract] [Full Text] [PDF]
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) and PERK-/- cells (
). The traces in A,B and the summary in C are the mean (black trace) ± s.e.m. (gray lines) of at least three experiments. All experiments were performed in the presence of 1 mM Ca2+o to enable measurement of the reloading.
indicates addition of 0.15 µM IP3; arrow indicates addition of 5 µM IP3). The results of three experiments are summarized in E and are given as the mean ± s.e.m.
