1 Department of Biological Sciences, National Sun Yat-sen University, No. 70, Lein-Hai Rd., Kaohsiung City, 804, Taiwan
2 Department of Pharmacology, College of Medicine, National Cheng Kung University, No.1, Ta-Hsueh Road, Tainan 701, Taiwan
3 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No.1, Ta-Hsueh Road, Tainan 701, Taiwan
* Author for correspondence (e-mail: netliou{at}mail.nsysu.edu.tw)
Accepted 27 July 2005
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Summary |
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Key words: Retinoic acid, Non-genomic, Transmitter release, Neuromuscular junction, Development
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Introduction |
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Successful synaptic transmission at the neuromuscular junction is a complex process regulated by interplay among intrinsic cellular programs, cell-cell and cell-substrate interactions, and plenty of soluble extracellular signaling molecules (Lu and Je, 2003). RA, which is highly expressed in the spinal cord of developing embryos, has been suggested to be capable of increasing the survival of developing motoneurons, stimulating neurite outgrowth and directing axons extending from embryonic spinal cord explants in vitro (Maden et al., 1998
; Prince and Carlone, 2003
). Apart from its known effect in patterning both the anteroposterior and dorsoventral axes, RA also has considerable significance as a neural differentiation factor. Recently, it has been suggested that RA, as an inductive signal, can direct embryonic stem cells to differentiate into motoneurons (Wichterle et al., 2002
). We have previously provided the first evidence that activation of `RARß' receptor is responsible for RA-induced rapid effect (
8-15 minutes) on spontaneous synaptic current (SSC) frequency facilitation at the developing neuromuscular synapse. Moreover, the insensitivity of RA-induced SSC frequency facilitation toward inhibitors of transcription and/or translation and the short time frame of their response further suggest the involvement of an unusual nongenomic mechanism (Liao et al., 2004
). Although results from our previous studies suggest that RA might act through a classical receptor to facilitate spontaneous neurotransmitter release by a non-classical mechanism, efforts are still needed to further explore the underlying molecular mechanisms through which RA induces facilitation of SSC frequency. How does RA enhance presynaptic efficacy? What are the intracellular signaling mechanisms that mediate such rapid synaptic effects of RA? It is well known that the intracellular Ca2+ concentration ([Ca2+]i) level in the nerve terminal exerts a dominant effect on the rate of spontaneous transmitter release (Augustine et al., 1987
). Many experimental approaches have suggested a regulatory role for steroid hormones in the control of [Ca2+]i. Aldosterone induces rapid increase in intracellular protein kinase C (PKC) activity and a rise of Ca2+ in human distal colon cells (Harvey et al., 2002
). In cultured skeletal muscle cells, 1,25-dihydroxyvitamin D3 produced a rise in [Ca2+]i by promoting a non-genomic release of Ca2+ from internal stores via activation of phospholipase C (PLC) and D and inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and by Ca2+ influx through L-type and store-operated Ca2+ channels (Capiati et al., 2001
). However, no information is available so far concerning the acute effects of RA on intracellular Ca2+ and on the turnover of membrane phosphoinositides. In the present study, we are seeking to fill these gaps in our understanding of the molecular machineries that are responsible for this facilitation. Results from our study show for the first time that RA rapidly triggers the liberation of Ca2+ from internal store, which is the result of pleiotropic convergent signaling pathways involving PLC
, phosphatidylinositide 3-kinase (PI 3-kinase) and activation of Src tyrosine kinase.
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Materials and Methods |
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One day following cell plating, functional synapses are rapidly established between cultured spinal neurons and embryonic muscle cells. The present study utilized synapses of myocytes innervated by single co-cultured spinal neurons. The frequency of spontaneous synaptic events during the first day of synaptogenesis was found to vary greatly from cell to cell, over two orders of magnitude, and the frequency of SSC events increased with time of synapse development (Evers et al., 1989). To test the facilitation effect induced by RA treatment in more simple conditions, our analyses were performed mostly in low-activity synapses (<1.0 Hz) to mimic the early contact between motoneurons and myocytes (Evers et al., 1989
). RA also facilitates, although to a lesser extent, the spontaneous transmitter release in neuromuscular synapse with higher activity (>1.5 Hz; data not shown).
Electrophysiology and data analysis
Gigaohm-seal whole-cell recording methods followed those described previously (Hamill et al., 1981) were used. Patch pipettes (Hilgenberg) were pulled with a two-stage electrode puller (PP-830, Narishige, Tokyo, Japan), and the tips were polished immediately before the experiment using a microforge (MF-830, Narishige). SSCs were detected from innervated myocytes by whole-cell recording in the voltage-clamp mode. Recordings were made at room temperature in Ringer's solution, and the solution inside the recording pipette contained 150 mM KCl, 1 mM NaCl, 1 mM MgCl2 and 10 mM Hepes (pH 7.2). Data were collected using a patch-clamp amplifier WPC-100 (ESF electronic, Göttingen, Germany) and Axoscope 8.0 (Axon). Signals were filtered at 10 KHz (Digidata 1322; Axon, Union City, CA). SSCs were detected and analyzed using the Mini Analysis Program 5.0 (Synaptosoft, Decatur, GA). To quantitatively measure the changes in neurotransmitter release, a time course of SSC frequency was first constructed on a minute-to-minute basis. The SSC frequencies for a 6-minute period right before drug application was averaged as control. The changes in SSC frequency were measured by averaging a 6-minute recording starting from the highest number after drug application (Liao et al., 2004
), and the results were expressed as mean ± s.e.m. The statistical significance was evaluated using Student's paired t-test.
Presynaptic loading of drug and fluorescent dye
Presynaptic spinal neurons were dialyzed using a patch pipette containing 150 mM KCl, 1 mM NaCl, 1 mM MgCl2, 10 mM Hepes, 5 mM GDPßS and 1 mg/ml of the fluorescent dye Lucifer Yellow while the whole-cell recordings were being made at the cell body. The dialysis of the drug and Lucifer Yellow could be visualized directly in the inverted microscope under fluorescence mode. After a 10-minute dialysis, the patch pipette was pulled off after damaging the seal by injection of a large hyperpolarizing current.
[Ca2+]i measurement with fura-2
[Ca2+]i was measured at room temperature with the fura-2 fluorescence ratio method on a single cell fluorimeter as previously described (Strotmann et al., 2000). In brief, cells attached on a coverslip were loaded with 2 µM fura-2/acetoxymethyl ester (fura-2/AM; Molecular Probes, Eugene, OR, USA) in DMEM culture medium at room temperature for 60 minutes. After loading, cells were washed three times with Ringer or Ca2+-free Ringer. After washing, coverslips were placed on the stage of an Olympus IX71 inverted microscope equipped with a xenon illumination system and an IMAGO CCD camera (Till Photonics, Grafelfing, Germany). The excitation wavelength was alternated between 340 nm and 380 nm using the Polychrome IV monochromator (Till Photonics, Grafelfing, Germany). The fluorescence intensity was monitored at 510 nm, stored digitally and analyzed using TILLvisION 4.0 (Till Photonics, Graefelfing, Germany) software. [Ca2+]i was represented as the ratio of F340/F380. F340 and F380 are the emissive fluorescence intensity when cell were excited at 340 nm and 380 nm.
Chemicals
The following chemicals were used: all-trans retinoic acid (RA), 8-(dethylamino) octyl 3,4,5-trimethoxybenzoate (TMB-8), Lucifer Yellow, 1,2-bis-(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxy-methyl) ester (BAPTA-AM), ruthenium red and thapsigargin were all obtained from Sigma (St Louis, MO, USA); PD98059, wortmannin, U73122, LY294002, bisindolmaleimide was from Tocris Cookson (Bristol, UK); Xestospongin C (XeC), 2-APB from Calbiochem (San Diego, CA, USA). All drugs were applied directly to the culture media at the times indicated.
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Results |
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The source of Ca2+ involved in synaptic potentiation induced by RA
This increase in [Ca2+]i may be due to influx of Ca2+ from the extracellular fluid or release of Ca2+ from intracellular stores. We first examined the role of Ca2+ influx in the action of RA. Ca2+ was eliminated from the culture medium after several washes with the Ca2+-free Ringer's solution. Treating the cells with RA still elicited an increase in SSC frequency under the zero external Ca2+ condition (Fig. 2A,C). The SSC frequency was increased by 29.6±6.4-fold (n=8) under the Ca2+-free condition. To further examine the role of membrane Ca2+ channels, we blocked Ca2+ influx by bath application of Cd2+ (0.5 mM), which competes with Ca2+ and blocks Ca2+ influx through Ca2+ channels. RA was still capable of facilitating SSC frequency in the presence of Cd2+ (20.1±7.3-fold of control, n=8, P<0.05; Fig. 2B,C). Thus, RA-induced facilitation of neurotransmitter release does not require Ca2+ influx from extracellular fluid.
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We next explored the routes of Ca2+ released from intracellular stores that resulted in RA-induced SSC frequency facilitation. Because of the possibility that depletion of internal Ca2+ might induce a Ca2+ entry through store-operated channels in the plasma membrane, the following experiments were performed, mainly in Ca2+-free medium to avoid unnecessary interference (Tempia et al., 2001). There are two major pathways that result in the release of Ca2+ from intracellular stores: the Ins(1,4,5)P3-sensitive and the ryanodine-sensitive Ca2+ stores (Berridge, 1998
). Preincubation of the culture for 15-20 minutes with membrane-permeable inhibitors of Ins(1,4,5)P3-induced Ca2+ release, XeC (1 µM) or 2-APB (50 µM), effectively blocked the increase of SSC frequency elicited by RA (Fig. 3A,B). The synaptic facilitation of RA under the presence of XeC and 2-APB was 5.1±1.5 (n=9) and 2.5±0.8 (n=6) times that of control, respectively. The release of Ca2+ from Ins(1,4,5)P3 receptors could further trigger Ca2+-induced Ca2+ release from ryanodine receptors. Pretreatment of the cultures with ryanodine receptor antagonist TMB-8 (3 µM) or ruthenium red (10 µM) blocked the action of RA (3.1±0.9, n=15 and 1.5±0.3, n=5, times the control values, for TMB-8 and ruthenium red pretreatment, respectively; Fig. 3C,D). Thus, an intracellular liberation of Ca2+ from both Ins(1,4,5)P3- and ryanodine-sensitive pools, rather than an influx of extracellular Ca2+, is responsible for the RA-induced synaptic facilitation.
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Mechanisms of RA action
How might RA come into play in mobilizing intracellular Ca2+ stores? To approach this problem, we examined the signaling pathway that is responsible for the action of RA in developing Xenopus neuromuscular synapses. Activation of PLC is an attractive candidate for the mediation of synaptic facilitation because its activation would result in intracellular Ca2+ release via the second messenger Ins(1,4,5)P3. To evaluate whether PLC is part of the RA signaling mechanism facilitating neurotransmitter release, we set out to examine the effect of inhibition of PLC on the action of RA. Pretreatment of cells with the PLC inhibitor U73122 (5 µM) prior to RA treatment completely blunted the RA-induced increase in SSC frequency (5.8±1.9-fold of control, n=5; Fig. 4A), suggesting that PLC
activity is required for RA-induced SSC frequency facilitation.
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Two possible mechanisms are indicated for PLC activation: PLCß by G protein-coupled receptor activation and PLC via kinase-mediated phosphorylation. PLC
is phosphorylated by diverse receptor tyrosine kinases and nonreceptor protein tyrosine kinases through a high affinity interaction with the SH2 domain of PLC
(Rhee, 2001
). Also, it has been shown that the binding of the PH domain of PLC
to phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] present in the membrane as a result of PI 3-kinase activation leads to the activation of PLC
(Bae et al., 1998
; Falasca et al., 1998
). To evaluate a possible participation of G protein in the RA-induced facilitating effects, GDPßS (a non-hydrolyzable GDP analogue and inhibitor of G protein) were used. Loading presynaptic neurons with the G protein inhibitor GDPßS (5 mM) prior to RA treatment did not affect the RA-induced SSC frequency facilitation (24.2±5.9-fold of control, n=5; Fig. 4B). These results suggest that the facilitating effects of RA on the spontaneous transmitter release are independent of a G protein serving as a signal transducer in the signaling pathway. Next, we addressed whether the inhibition of PI 3-kinase by its specific inhibitor wortmannin would impair RA-induced SSC frequency facilitation. The RA-induced SSC frequency facilitation was abolished in the presence of wortmannin (100 nM; 1.2±0.2-fold of control, n=8; Fig. 4C). Pretreatment with another PI 3-kinase inhibitor, LY294002 (5 µM), also prevented the RA-induced increase in SSC frequency (1.1±0.2-fold of control, n=7; Fig. 4D).
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Discussion |
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With regard to a possible involvement of Ca2+ in the rapid regulatory role of RA in spontaneous synaptic transmission, the following findings of the nongenomic effects of steroid hormones and other lipophilic agents such as thyroid hormones should be mentioned. Aldosterone induces rapid increase in intracellular PKC activity and a rise of Ca2+ in human distal colon cells (Doolan et al., 1998). In cultured skeletal muscle cells, 1,25-dihydroxyvitamin D3 produced a rise in [Ca2+]i by promoting a non-genomic release of Ca2+ from internal stores via activation of PLC and D and Ins(1,4,5)P3 receptor and by Ca2+ influx through L-type and store-operated Ca2+ channels (Capiati et al., 2001
). Furthermore, Dufy-Barbe et al. (Dufy-Barbe et al., 1992
) showed an increased Ca2+-dependent spiking activity in pituitary cells after estradiol application. Here we show the first evidence that events leading to the RA-induced synaptic facilitation involve PLC
, PI 3-kinase and activation of Src tyrosine kinase. Activation of PLC
is an attractive candidate for the mediation of synaptic facilitation because its activation would result in intracellular Ca2+ release via the second messenger Ins(1,4,5)P3. There are two possible mechanisms that resulted in PLC
activation. PLC
is phosphorylated by diverse receptor tyrosine kinases and nonreceptor protein tyrosine kinase through a high affinity interaction with its SH2 domain (Rhee, 2001
). It has also been shown that the binding of the PH domain of PLC
to phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] present in the membrane as a result of PI 3-kinase activation leads to the activation of PLC
(Falasca et al., 1998
; Bae et al., 2001). Results in our experiments show that either the PI 3-kinase inhibitor or the PLC
inhibitor can effectively prevent the synaptic facilitation and [Ca2+]i rise induced by RA, suggesting that PLC
activated from the PI 3-kinase pathway appears to play an important role. How might RA come into play in activation of PI 3-kinase? PI 3-kinase, a heterodimeric complex composed of a regulatory 85-kDa and catalytic 110 kDa subunit, is typically activated by receptors with an intrinsic or associated protein tyrosine kinase activity, proteins that are tyrosine-phosphorylated in response to external stimuli, and by G protein-coupled receptors (Leevers et al., 1999
). Although the usual action of RA is transcriptional regulation, our results, on the basis of the rapid RA-induced synaptic facilitation, suggest that RA may activate PI 3-kinase through a nongenomic action of its receptor. This is in line with an increasing number of other studies, which suggest the nongenomic activation of PI 3-kinase by steroid hormones and other lipophilic agents such as thyroid hormones. The involvement of PI 3-kinase activation in vitamin D3-induced myeloid cell differentiation and progesterone-induced oocyte maturation in Xenopus has been reported (Hmama et al., 1999
; Hehl et al., 2001
). Furthermore, others have demonstrated that 17ß-estradiol induces the nongenomic activities of its receptor ER
to evoke the PI 3-kinase/AKT signaling pathway committed to the regulation of cell proliferation (Acconcia et al., 2004). In further support of this hypothesis, it has recently been suggested that an extragenomic activation of PI 3-kinase by RA is required for neural differentiation of SH-SY5Y human neuroblastoma cells (Lopez-Carballo et al., 2002
).
An important mechanistic question that arises from the results shown here is the nature of the molecular mechanism by which RA activates PI 3-kinase. Much to our surprise, while trying to go further into the mechanisms that relay the signal from the RA receptor to PI 3-kinase, we found the first evidence of the participation of Src tyrosine kinase in the synaptic facilitating effect of RA. Preincubation of the cultures with pharmacological inhibitors genistein, a broad-spectrum tyrosine kinase inhibitor, or PP2, which predominantly inhibits the Src family of nonreceptor tyrosine kinase, completely abolished RA-induced synaptic facilitation and rise in [Ca2+]i. It is known that nonreceptor tyrosine kinases, such as JAKs, Syk, Src and ZAP70, which are recruited and activated by a variety of receptors, are involved in regulation of PI 3-kinase activity (Cantrell, 2001). For example, there are compelling results showing that Src kinase, acting through a PI 3-kinase-dependent pathway, is required for neuronal survival and neurite outgrowth, suggesting that Src kinase may be involved in the regulation of PI 3-kinase activity in the nervous system (Encinas et al., 2001
). Although there is no information in the literature to date concerning the association of Src kinase and the RA receptor, it is worthwhile to note that there is increasing evidence on the role and biological significance of the Src family of nonreceptor tyrosine kinase within the rapid, nongenomic action of steroid and thyroid hormones (Shupnik, 2004
). There is evidence indicating that in chick skeletal muscle cells, 1
, 25 dihydroxyvitamin D3 promotes complex formation between vitamin D receptor and Src kinase and is thus responsible for the rapid modulation of Ca2+ influx by opening both L-type voltage-dependent and store-operated Ca2+ channels (Buitrago et al., 2001
). In rat enterocytes, the Src kinase is involved in parathyroid hormone-dependent PI 3-kinase activation (Gentili et al., 2002
). It has been suggested that Src kinase plays a central role in estrogen and progesterone-dependent PI 3-kinase and MAPK activation (Migliaccio et al., 1996
). Moreover, recent results from binding assays revealed that the estrogen receptor interacted with the SH2 domain of Src, whereas the androgen receptor and progesterone receptor interacted with SH3 domain of Src kinase (Boonyaratanakornkit et al., 2001
). Precisely how Src kinase couples the RA receptor to PI 3-kinase remains a subject for further study. A possible mechanism by which RA stimulates Src activity in Xenopus developing neuromuscular synapses may be to bind RA to its receptor, thus inducing a conformational change on this protein, which is then sensed by the Src kinase. We have previously provided evidence that the activation of RARß receptor is responsible for RA-induced SSC frequency facilitation (Liao et al., 2004
). It could be informative in the future to explore, by the use of amino acid alignments and crystal structure analysis, if there is a Src kinase-binding motif in RARß.
A rich history of research dating back to the time of Hans Selye (1942) supports the observations that apart from the generally accepted theory of action of the steroid-thyroid-retinoid hormone nuclear receptor superfamily, there also exists a nongenomic action mechanism in many steroids. Much of our knowledge about the nongenomic effect of the nuclear receptor superfamily comes from the studies of steroid hormones; however, no information is available for the nongenomic effects of RA. During development, the RA receptors are present in developing motoneurons, and high levels of RA have been detected in the spinal cord (Maden et al., 1998). In addition to its acknowledged role in patterning both the anteroposterior and dorsoventral axes, compelling evidence has suggested that RA also has considerable significance as a neural differentiation factor (Maden et al., 1998
; Prince and Carlone, 2003
).
Previously we have shown the first physiological evidence that RA potentially enhances the spontaneous transmitter release at the developing neuromuscular synapses. Here our results provide not only a deeper insight in understanding the activation of Src kinase/PI 3-kinase as a novel signaling pathway in response to RA, but also open up an entirely new area of investigation in the field of nongenomic regulation of synaptic function elicited by RA, since these rapid changes in synaptic activity may represent a mechanism whereby synapse formation is initiated. What is the functional significance of facilitating ACh secretion by RA during the early phase of synaptogenesis? Neuronal activity at developing synapses is crucial in synapse maturation and competition as well as in the differentiation of postsynaptic properties (Balice-Gordon and Lichtman, 1993). The potentiation of the spontaneous ACh release at developing neuromuscular synapses may have profound developmental significance. Several studies have indicated that the gene expression and secretion of neurotrophic factors NT-3 and NT-4 in the neuromuscular junction are regulated by synaptic activity (Liou and Fu, 1997
; Xie et al., 1997
). It has also been suggested that activity-dependent secretion of neurotrophic factors is important in synaptic activity regulation and may be involved in Hebbian-type homosynaptic potentiation (Poo, 2001
). Furthermore, SSCs at developing neuromuscular junctions in Xenopus cultures are capable of eliciting action potentials and spontaneous contractions in muscle cells. This frequent supra-threshold excitation produces a global influence on the development of contractile properties of the postsynaptic muscle cell. In addition, spontaneous synaptic potentials are accompanied by a localized influx of ions, including Ca2+, at the subsynaptic site of the muscle (Decker and Dani, 1990
). Local Ca2+ accumulation and the consequent Ca2+-dependent enzymatic reactions are likely to play an important role in regulating the development of postsynaptic structure. Overall, conclusions drawn from current studies suggest that RA rapidly elicits synaptic facilitation through mobilizing Ca2+ from Ins(1,4,5)P3 and/or ryanodine-sensitive intracellular Ca2+ stores of the presynaptic nerve terminal. This involves consecutive activation of pleiotropic signaling molecules including PLC
, PI 3-kinase and Src kinase, leading to an enhancement of spontaneous transmitter release. It thus may have significant roles in initiating the consecutive and complex cross-interaction between presynaptic motoneurons and postsynaptic muscle cells that then lead to the maturation of the neuromuscular synapse.
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Acknowledgments |
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