Institute of Biomedical and Life Sciences, Neuroscience and Biomedical Systems, West Medical Building, University of Glasgow, Glasgow, G12 8QQ, UK
* Author for correspondence (e-mail: J.McCarron{at}bio.gla.ac.uk)
Accepted 23 August 2005
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Summary |
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Key words: Ca2+ signalling, Smooth muscle, FKBP12, IP3 receptors
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Introduction |
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IP3R activity is regulated by accessory proteins such as calmodulin (Taylor and Laude, 2002; Kasri et al., 2002
), certain neuronal Ca2+-binding proteins (Yang et al., 2002; Kasri et al., 2004
) and the anti-apoptotic protein Bcl-2 (Chen et al., 2004
). The 12 kDa FK506-binding protein, FKBP12 also interacts with IP3R to regulate IP3-mediated Ca2+ release (Cameron et al., 1995b
; Dargan et al., 2002
), athough this has been disputed (Bultynck et al., 2001a
; Bultynck et al., 2001b
; Carmody et al., 2001
). FKBP12 reportedly increases, decreases or has no effect on IP3-mediated Ca2+ release, even when bound to the receptor. With regard to FKBP12's binding to the receptor, neither solubilised IP3R nor proteolytic fragments containing IP3R combined with glutathione-S-transferase (GST)-FKBP12 Sepharose columns, though RyR did so (Bultynck et al., 2001a
; Carmody et al., 2001
; Zheng et al., 2004
). IP3R also did not co-immunoprecipitate or co-purify with FKBP12 in cerebellar microsomes (Bultynck et al., 2001a
; Thrower et al., 2000
). Yet, in other co-immunoprecipitation, co-purification and direct-binding-assay studies, FKBP12 was tightly bound to IP3R in rat cerebellum (Cameron et al., 1995a
; Cameron et al., 1995b
). Further studies using the yeast two-hybrid system, showed the binding of FKBP12 to the IP3R and located the site of binding to the leucyl-proline dipeptide residues 1400-1401 (Cameron et al., 1997
).
Results from functional studies of IP3R modulation by FKBP12 are also controversial. The association between FKBP12 and IP3R is disrupted by immunosuppressant drugs, such as FK506 and rapamycin, that bind to FKBP12 to form drug-immunophilin protein complexes, which then displace the accessory proteins from the channel (Cameron et al., 1995b; Cameron et al., 1997
; Dargan et al., 2002
). Whereas FK506 abolished ATP-induced Ca2+ oscillations in tracheal epithelial cells, thereby suggesting a modulating role for FKBP12 in IP3 release (Kanoh et al., 1999
), no functional effect of FK506 or FKBP12 on IP3-induced Ca2+ release has emerged in A7r5, SH-SY5Y, C2C12 or COS-7 cells (Bultynck et al., 2001a
; Boehning and Joseph, 2000
; Bultynck et al., 2000
). Even where functional effects of FKBPs in IP3-evoked Ca2+ release have been claimed, controversy persists. In some studies, removal of FKBP12 from IP3R increased (Cameron et al., 1995b
; Cameron et al., 1997
), whereas in others the addition of FKBP12 to IP3R increased the activity of the channel (Dargan et al., 2002
). In the former studies, disruption of FKBP12 binding to IP3R increased the activity of the channel (Cameron et al., 1995b
). In the latter study, recombinant FKBP12, when added to the purified cerebellar IP3R1 isoform incorporated into planar bilayers, substantially increased the activity of the channel and induced `coordinated gating' of neighbouring receptors (Dargan et al., 2002
), an effect reversed by FK506.
One explanation for the apparent controversy might be FKBP12's ability to regulate IP3R indirectly (Cameron et al., 1995a). Displacement of FKBP12 from IP3R by FK506 results in the formation of an FK506-FKBP12 complex that binds to and inhibits the Ca2+/calmodulin-dependent phosphatase calcineurin (Liu et al., 1991
). Indeed, calcineurin inhibition might mediate FK506's immunosuppressant actions (Liu et al., 1992
). FKBP12 might localise calcineurin to the IP3R to regulate the phosphorylation status of the channel (Cameron et al., 1995a
; Kawamura and Su, 1995
). Indeed, in cerebellum, the physical association of calcineurin with the IP3R-FKBP12 complex is displaced by FK506 (Cameron et al., 1995a
; Cameron et al., 1997
). This association increases IP3R phosphorylation and enhances Ca2+ release (Cameron et al., 1995a
). Again, in adrenal glomerulosa cells, both Ca2+ signalling and protein kinase C (PKC)-mediated phosphorylation of the IP3R were modified by FK506 (Poirier et al., 2001
), whereas in COS-7 cells, calcineurin reduced IP3-induced Ca2+ release, an effect reversed by FK506 (Bandyopadhyay et al., 2000
). However, as with FKBP12, the mechanisms by which calcineurin regulates Ca2+ release from IP3R are disputed. Indeed, calcineurin might regulate Ca2+ release independently of FKBP12 (Bultynck et al., 2003
) or, in other cases, not at all (Kanoh et al., 1999
). In the latter study, in airway epithelial cells, FK506 attenutated ATP-induced Ca2+ oscillations, whereas calcineurin inhibitors did not.
FKBPs are also displaced from the IP3R by the bacterially-derived antibiotic rapamycin from Streptomyces hygroscopicus (Marks, 2003). Rapamycin was originally used as an antifungal agent but has since been discarded because of its undesirable immunosuppressive side effects. These side effects were subsequently explored and developed and the drug was approved for clinical use as an immunosuppressant (e.g. Marks, 2003
; Barshes et al., 2004
). The intracellular receptor for rapamycin is FKBP12 but the complex so formed does not inhibit calcineurin (unlike the FK506-FKBP12 complex). The molecular target for the rapamycin-FKBP12 complex is the protein kinase `target of rapamycin' (TOR), its mammalian homologue is called mTOR (Heitman et al., 1991
). mTOR is a phosphatidyl inositol-related kinase that is inhibited by the rapamycin-FKBP12 complex. mTOR integrates signals from nutrients (amino acids and energy) and growth factors (in higher eukaryocytes) to regulate and coordinate cell growth and cell-cycle progression (reviewed by Panwalkar et al., 2004
). Although no direct experimental link between mTOR and IP3-mediated Ca2+ release has been established so far, rapamycin itself reportedly decreased Ca2+ release from cerebellar microsomes (Dargan et al., 2002
) even though the proposed mechanism did not involve mTOR.
In view of the potential importance of FKBP12 in regulating IP3-mediated Ca2+ release, with accompanying consequences for Ca2+ signalling and the persistent controversy regarding the interaction between IP3R and accessory proteins the present study was undertaken. We propose here, mechanisms by which FKBP12 regulates IP3-evoked Ca2+ release in smooth muscle. Freshly isolated single colonic smooth muscle cells were selected; IP3-evoked Ca2+ release does not activate RyRs in this cell type (Flynn et al., 2001; McCarron et al., 2004a
), simplifying the analysis of results. Cells were voltage-clamped in the whole-cell-configuration to avoid [Ca2+]c changes that might occur through Ca2+ influx as a result of changes of the membrane potential, evoked by rapamycin or FK506. The use of flash-photolysis of caged IP3 minimised the activation of second messenger systems to give a clearer understanding of the control of Ca2+ release from the receptors. The study found that mTOR inhibitors - including rapamycin - that operate through FKBP12, inhibited IP3-mediated Ca2+ release. However, calcineurin inhibitors operating through FKBP12, including FK506, increased Ca2+ release; FK506 was ineffective after calcineurin had been blocked. In aortic smooth muscle, in which FKBP12 did not associate with the receptor, neither rapamycin nor FK506 altered IP3-mediated Ca2+ release. We propose that, when associated with the receptor, FKBP12 itself has little direct effect on IP3R but potentiates Ca2+ release by inhibiting calcineurin or reduces Ca2+ release by blocking mTOR.
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Materials and Methods |
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Methods
Cell dissociation
Male guinea pigs were killed by cervical dislocation with immediate exsanguination in accordance with the Animal (Scientific Procedures) Act 1986, UK. Single smooth-muscle cells were enzymatically isolated from the guinea-pig colon or aorta, stored at 4°C and used on the same day (McCarron and Muir, 1999). All experiments were conducted at room temperature (20-22°C). Cells were voltage-clamped using conventional tight-seal whole-cell recording. The composition of the extracellular solution was: Na-glutamate (80 mM), NaCl (40 mM), tetraethylammonium chloride (TEA) (20 mM), MgCl2 (1.1 mM), CaCl2 (3 mM), HEPES (10 mM), and glucose (30 mM) (pH 7.4 adjusted with 1 M NaOH). The pipette solution contained: (Cs)2SO4 (85 mM), CsCl (20 mM), MgCl2 (1 mM), HEPES (30 mM), pyruvic acid (2.5 mM), malic acid (2.5 mM), KH2PO4 (1 mM), MgATP (3 mM), creatine phosphate (5 mM), guanosine triphosphate (0.5 mM), fluo-3 penta-ammonium salt (0.1 mM) and caged Ins(1,4,5)P3-trisodium salt (caged IP3) (0.025 mM) (pH 7.2 adjusted with 1 M CsOH). Whole cell currents were amplified by an Axopatch 1D amplifier (Axon instruments, Union City, CA, USA), low pass filtered at 500 Hz (eight-pole bessel filter; Frequency Devices, Haverhill, MA), and digitally sampled at 1.5 kHz using a Digidata interface, pCLAMP software (version 6.0.1, Axon Instruments) and stored on a personal computer for analysis.
[Ca2+]c was measured as fluorescence from the membrane-impermeable dye Fluo-3 introduced into the cell through the patch pipette (McCarron and Muir, 1999). To photolyse caged IP3 (25 µM), the output of a xenon flashlamp (Rapp Optoelektronik, Hamburg, Germany) was passed through a UG-5 filter to select UV light and merged into the excitation light path of the microfluorimeter using the second arm of the quartz bifurcated fibre-optic bundle (McCarron and Muir, 1999
) and applied to the caged compound. Fluorescence signals were expressed as ratio (F/F0) of fluorescence counts (F) relative to baseline (control) values (taken as 1) before stimulation (F0).
Immunoprecipitation and western blotting
All procedures were performed at 4°C. Freshly isolated and hand-homogenised smooth muscle from guinea pig colon or aorta was solubilised (Cameron et al., 1995a), but using a lower concentration of Triton X-100 (0.2% Triton X-100 for 60 minutes), which, when combined with low speed centrifugation (1500 g for 10 minutes), minimised mechanical and chemical inhibition of FKBP interactions with receptors (Carmody et al., 2001
; Dargan et al., 2002
; George et al., 2003
). IP3R protein was immunoprecipated from 500 µg (total protein) samples of this preparation by overnight incubation with rabbit anti-IP3R antibody (Affinity BioReagents, Golden, USA) followed by incubation with protein G-sepharose for a further 30 minutes. The sepharose beads were then washed and IP3Rs eluted by heating at 70°C in 4x Laemmli sample buffer.
Sodium dodecyl sulphate gel electrophoresis (SDS-PAGE) was performed as described by Currie and Smith (Currie and Smith, 1999), except that 3-8% Tris-acetate gels were used for IP3R and calcineurin A detection, and 12% Bis-Tris gels for FKBP12 and calcineurin B detection. Recombinant FKBP12 (for FKBP12 protein) and non-immunopreciptated solubilised supernatant (for IP3R, calcineurin A and calcineurin B proteins) served as positive controls. Proteins were detected with specific rabbit primary antibodies against IP3R, FBKP12, calcineurin B (each from Affinity BioReagents, Golden, USA), mTOR (Cell Signalling Technology Inc., Beverly, USA), and with mouse monoclonal anti-calcineurin A (Sigma, Poole, Dorset, UK) followed by incubation with HRP-conjugated anti-rabbit or anti-mouse secondary antibodies (Sigma, Poole, UK). Blots were developed using the enhanced chemiluminescence (ECL) detection system (Amersham Bioscences, Amersham, Bucks, UK). Qentix was used as a western-blot enhancer for FKBP immunoblots (Pierce Biotechnology, Rockford, USA).
Statistical analysis
Results are expressed as means ± s.e.m. Student's t-test was applied to test and control conditions, a value of P<0.05 was considered significant.
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Results |
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In contrast to the results with rapamycin, FK506 (10 µM), which inhibits both the FKBP12-IP3R interaction and calcineurin but not mTOR (Cameron et al., 1995b; Cameron et al., 1997
; Dargan et al., 2002
), significantly (P<0.05) increased IP3-mediated Ca2+ release in voltage-clamped single smooth-muscle cells by 30±10% (
F/F0 from 2.05±0.19 to 2.67±0.31, n=11, Fig. 4). This difference might have occurred because FK506, unlike rapamycin, inhibits the Ca2+-activated phosphatase calcineurin, whereas FK506 and rapamycin each disrupt FKBP12 interaction with IP3R1. If so, then the potentiation of Ca2+ release by FK506 might be mediated by the inhibition of calcineurin. To examine this, the effects of calcineurin inhibition on IP3-evoked Ca2+ release were studied. Photolysed caged IP3 reproducibly increased [Ca2+]c in these cells. The calcineurin inhibitor cypermethrin (10 µM) and the protein phosphatase inhibitor okadaic acid (5 µM each significantly (P<0.001 and P<0.05, respectively) increased this rise in Ca2+ (
F/F0) by 85±23% and 33±12%, from 0.45±0.1 to 0.74±0.11 and from 0.85±0.22 to 1.03±0.23, respectively (n=12 and 8, respectively (Fig. 5A and Fig. 5B, respectively), suggesting that calcineurin regulates the phosphorylation state of the IP3R (Cameron et al., 1995a
). Significantly, cypermethrin, okadaic acid and the calcineurin inhibitory peptide (CiP) each prevented the FK506-induced increase in IP3R-mediated Ca2+ release (Fig. 6A-C). Thus, in the presence of 100 µM CiP (where CiP was administered into the cell through the pipette solution because it is impermeant), FK506 (10 µM) did not significantly alter the IP3-evoked Ca2+ transient (
F/F0 from 1.43±0.42 to 1.54±0.46 in the additional presence of FK506, n=11, P>0.05; Fig. 6A). After cypermethrin, the IP3-evoked Ca2+ increase was also unaltered by FK506 (Fig. 6B;
F/F0 was 1.1±0.17 in cypermethrin and 0.99±0.17 in the additional presence of FK506, n=6, P>0.05). After incubation with okadaic acid, the Ca2+ increase was also unaltered by FK506 (Fig. 6C;
F/F0, 1.94±0.33 in okadaic acid and 1.89±0.38 in the additional presence of FK506, n=7, P>0.05). IP3-mediated Ca2+ release was not maximally activated in the presence of the phosphatase inhibitors. Thus, the thiol-reactive agent thimerosal, which potentiates IP3-mediated Ca2+ release (e.g. Bootman et al., 1992
), increased IP3-mediated Ca2+ release by a further 14±2% (n=4, P<0.05) after the phosphatase inhibitor cypermethrin. In these experiments IP3 evoked a
F/F0 increase of 0.97±0.49 in control cells, 1.77±0.63, in cypermethrin (10 µM) alone, and 1.99±0.69 in cypermethrin (10 µM) and thimerosal (100 µM) (n=4). Together, these results suggest that FK506 potentiates IP3-mediated Ca2+ release by inhibition of calcineurin.
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In aortic smooth muscle the interaction between FKBP12 and IP3R was also studied by immunoprecipitation from solubilised guinea-pig aorta homogenates. Here aortic smooth muscle, FKBP12 was expressed at similar levels to those occurring in colon (Fig. 7A), however it did not co-immunoprecipitate with IP3R (Fig. 7B,C). Also, rapamycin (10 µM) or FK506 (10 µM) did not significantly (P>0.05) alter IP3-induced Ca2+ release in voltage-clamped single aortic smooth-muscle cells (Fig. 7D,E). Thus, F/F0 was 0.9±0.28 in control and 0.86±0.26 in FK506 (10 µM; n=6) and, in separate experiments,
F/F0 was 1.26±0.55 in control and 1.18±0.52 in rapamycin (10 µM; n=3).
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Discussion |
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Rapamycin disrupts the binding of FKBP12 to the receptor and together with FKBP12 inhibits mTOR. Like the mTOR inhibitors RAD001 and LY294002 (the latter also inhibits phosphoinositide 3-kinase) rapamycin also reduces IP3-mediated Ca2+ release. These results are unlikely to be due to a reduced luminal SR [Ca2+]l by virtue of SR Ca2+ pump inhibition (Bultynck et al., 2000; Bilmen et al., 2002
), because the Ca2+ increase evoked by RyR activation (by caffeine) was increased by rapamycin, indicating the adequacy of the Ca2+ content of the SR. In our experiments, IP3R was activated directly by photolysis of caged IP3, so obviating the signal transduction pathway that mediates IP3 synthesis. The inhibition by rapamycin cannot be explained by an indirect block of IP3-mediated Ca2+ release caused by an altered sarcolemma membrane potential (Weidelt and Isenberg, 2000
) because all cells were voltage-clamped. A reversal of the potentiating effect of FKBP12 on IP3R activity by rapamycin as reported by Dargan et al. (Dargan et al., 2002
), is also unlikely to account for the present findings because the removal of FKBP12 by FK506 had no effect on IP3-mediated Ca2+ release after calcineurin inhibition. Taken together, these results suggest an important role for mTOR in regulating IP3-mediated Ca2+ release but the mechanisms involved remain unclear.
Our findings show that FKBP12 colocalised with the IP3R in colonic myocytes, although whether or not this is a direct interaction is unclear. Some reports by other investigators confirm, whereas others dispute, a physical interaction between FKBP12 and IP3R. For example, although the type 1 IP3R contains a consensus sequence for FKBP12 binding, it failed to immobilise FKBP12 (Bultynck et al., 2001a), suggesting no physical interaction between them. However, our study and those of others have shown a physical interaction between IP3R and FKBP12 (Cameron et al., 1995a
; Cameron et al., 1995b
). Methodological differences could explain these apparently contradictory results. Detergents, high-speed centrifugation and high temperatures have each already been shown to disrupt the interaction between RyR and FKBP (Dargan et al., 2002
; George et al., 2003
), and this might also apply to the interaction between IP3R and FKBPs. The position of a cell in its life cycle (Bultynck et al., 2001a
) or its signalling status (Carmody et al., 2001
), e.g. the extent of phosphorylation of the IP3R - as with FKBP12.6 and RyR (Marx et al., 2000
) - might also determine whether or not FKBP12 is bound to IP3R. Moreover, species or tissue differences might also provide an explanation for the variation in results. Indeed, in this study, in experimental conditions in which FKBP12 co-immunoprecipitated with IP3R in colon cells, no association between the receptor and FKBP12 was seen in aortic smooth muscle. Furthermore, neither rapamycin nor FK506 altered IP3-mediated Ca2+ release in intact cells from this tissue, suggesting that absence of association was not a result of a disrupted interaction between FKBP12 and IP3R caused by co-immunoprecipitation methods.
In this study, calcineurin also co-immunoprecipitated with IP3R in colonic myocytes. However, the colocalization of calcineurin does not appear to require FKBP12 because FK506 did not reduce the binding of calcineurin to IP3R. In colonic myocytes, unlike in brain membranes (Cameron et al., 1995b), FKBP12, calcineurin and IP3R might not exist in a trimeric complex.
The IP3R is phosphorylated by multiple serine/threonine protein kinases, including cAMP-dependent protein kinase and PKC, to increase the activity of the channel (reviewed by Patterson et al., 2004). The serine/threonine protein kinase mTOR is a member of the phosphoinositol kinase-related kinase family (reviewed by Panwalkar et al., 2004
) and involved in the regulation of cell growth by initiating gene translation in response to nutrients such as ATP, amino acids (mainly leucine), growth factors, insulin and mitogens. mTOR might also be involved in a diversity of additional cellular functions, including actin organization, secretion, membrane activity and PKC signalling (reviewed by Panwalkar et al., 2004
). The present results imply that, among its multiple and diverse effects, mTOR also regulate IP3Rs. This activity might be supported by the localization of the kinase to the internal Ca2+ store (Drenan et al., 2004
). However, whether this is a direct effect of mTOR on the IP3R, or an indirect action, e.g. by cyclin-dependent protein kinase or PKC (Yonezawa et al., 2004
; Malathi et al., 2003
) remains to be established. mTOR might sense cellular ATP levels and suppress protein synthesis when these levels decrease (reviewed by Proud, 2002
; Houghton and Huang, 2004
; Jaeschke et al., 2004
), i.e. mTOR might act as a nutrient sensor for the cell. Rapamycin, by inhibiting mTOR, will mimic the conditions of nutritional depletion. Although the full functional significance of the potentiating effect of mTOR on IP3R channel activity is still unknown, it is tempting to suggest from our present findings that mTOR maintains Ca2+ release from IP3Rs when the nutritional status of the cell is adequate, whereas in nutritionally-depleted conditions, IP3-mediated Ca2+ release is reduced to conserve ATP use like, for example, following inhibition of Ca2+ pump activity in store refilling.
Different effects of rapamycin and FK506 on cell signalling highlighted in this study are already recognised in other contexts. For example, rapamycin inhibits smooth muscle proliferation, whereas FK506 does not (Poon et al., 1996). Here, we propose another example of different, indeed opposite, effects of FKBPs as revealed by FK506 and rapamycin on signals derived from IP3R. The diversity of roles played by FKBP12 is achieved in part because FKBP12 has no direct effect on the activity of the IP3R but might either increase or decrease Ca2+ release indirectly, depending on the effectors present (calcineurin or mTOR).
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Acknowledgments |
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