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1.
M. Sendtner P. Carrol B. Holtmann R. A. Hughes H. Thoenen 《Developmental neurobiology》1994,25(11):1436-1453
Ciliary neurotrophic factor (CNTF) was first identified and partially purified from embryonic chick eye tissues. Subsequently, it was shown that CNTF is also present in large amounts in sciatic nerves of adult rats and rabbits, which led to its final purification and cloning. CNTF is not secreted by the classical secretory pathway involving the endoplasmatic reticulum and Golgi complex, but can be detected in high quantities within the cytoplasm of myelinating Schwann cells and astrocytes using immunohistochemistry. CNTF supports survival and / or differentiation of a variety of neuronal cell types including sensory, sympathetic and motoneurons. Also, nonneuroanl cells, such as oligodendrocytes, microglial cells, liver cells, and skeletal muscle cells, respond to exogenously administered CNTF, both in vitro and in vivo. During development, expression of CNTF is very low, if indeed it is expressed at all, and the phenotype of mice lacking endogenous CNTF, suggesting that CNTF after inactivation of the CNTF gene by homologous recombination suggests that CNTF does not play a crucial role for responsive cells during embryonic development. However, motoneurons are lost postnatally in mice lacking endogenous CNTF, suggesting that CNTF acts physiologically on the maintenance of these cells. The ability of exogenous CNTF to protect against motoneuron loss following lesion or in other animal models indicates that CNTF might be useful in the treatment of human motoneuron disorders, provided appropriate means of administration can be found. 1994 John Wiley & Sons, Inc. 相似文献
2.
Duff E Li CL Hartzell DL Choi YH Della-Fera MA Baile CA 《Apoptosis : an international journal on programmed cell death》2004,9(5):629-634
Recent findings show that ciliary neurotrophic factor (CNTF) and leptin have similar effects on food intake and body weight, suggesting possible overlapping mechanisms. Intracerebroventricular (icv) injection of leptin results in adipose tissue apoptosis. To determine if CNTF has similar activity, male Sprague Dawley rats implanted with lateral cerebroventricular cannulas were randomly assigned to four treatment groups ( N = 8), including control (aCSF), 10 microg/day leptin, 1 microg/day CNTF, and 5 microg/day CNTF. Rats received daily icv injections for 4 successive days. Both leptin and CNTF (5 microg) decreased BW (8.6% and 11.77%, respectively, p <.05) and cumulative food intake was decreased 43% by leptin ( p <.05). Leptin and CNTF (5 microg) reduced adipose tissue mass in epididymal adipose (Epi) by 30 and 33.5%, ( p <.05), in inguinal adipose (Ing) by 51 and 55% ( p <.05), in retroperitoneal adipose (Rp) by 65 and 64% ( p <.05), and in intrascapular brown adipose (iBAT) by 34 and 25% ( p <.05), respectively. Gastrocnemius muscle was not affected. Leptin and CNTF (5 microg) increased apoptosis in Epi by 84 and 150%, respectively ( p <.05) and in Rp by 121 and 146%, respectively ( p <.05). Loss of adipocytes by apoptosis may provide an explanation for the unexpected delay in return to initial energy status following CNTF treatments. 相似文献
3.
Ciliary neurotrophic factor induces cholinergic differentiation of rat sympathetic neurons in culture 总被引:14,自引:3,他引:11
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Ciliary neurotrophic factor (CNTF) influences the levels of choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH) in cultures of dissociated sympathetic neurons from newborn rats. In the presence of CNTF both the total and specific activity of ChAT was increased 7 d after culture by 15- and 18-fold, respectively, as compared to cultures kept in the absence of CNTF. Between 3 and 21 d in culture in the presence of CNTF the total ChAT activity increased by a factor of greater than 100. Immunotitration demonstrated that the elevated ChAT levels were due to an increased number of enzyme molecules. In contrast to the increase in ChAT levels, the total and specific activity levels of TH were decreased by 42 and 36%, respectively, after 7 d in culture. Half-maximal effects for both ChAT increase and TH decrease were obtained at CNTF concentrations of approximately 0.6 ng and maximal levels were reached at 1 ng of CNTF per milliliter of medium. The effect of CNTF on TH and ChAT levels were seen in serum-containing medium as well as in serum-free medium. CNTF was shown to have only a small effect on the long-term survival of rat sympathetic neurons. We therefore concluded that the effects of CNTF on ChAT and TH are not due to selective survival of cells that acquire cholinergic traits in vitro, but are rather due to the induction of cholinergic differentiation of noradrenergic sympathetic neurons. 相似文献
4.
Tyrosine hydroxylase (TH) is the rate-limiting enzyme in norepinephrine synthesis, and its expression and activity are regulated by many factors in sympathetic neurons. Cytokines that act through gp130, such as ciliary neurotrophic factor (CNTF) decrease norepinephrine production in sympathetic neurons by suppressing TH mRNA and stimulating degradation of TH protein, leading to the loss of enzyme. Their effect on the activity of TH is unclear, but recent in vivo observations suggest that cytokines may stimulate TH activity. We investigated this issue by quantifying TH protein levels and activity in cultured sympathetic neurons. We also examined the state of TH phosphorylation on serine 31 and 40, sites known to affect TH activity and degradation. We found that CNTF, acting through gp130, stimulated the rate of l-3,4-dihydroxyphenylalanine production while at the same time decreasing TH enzyme levels, thereby increasing the specific activity of the enzyme. We also found that phosphorylation of TH on Ser31 was increased, and phosphorylation on Ser40 was decreased, after four days of CNTF exposure. Our data are consistent with previous findings that Ser31 phosphorylation stimulates TH activity, whereas Ser40 phosphorylation can target TH for proteasomal degradation. 相似文献
5.
《Progress in growth factor research》1992,4(2):139-155
Ciliary neurotrophic factor (CNTF), originally identified for its ability to promote survival of neurons of the ciliary ganglion, is now known to have additional survival and differentiative actions on cells of the nervous system. CNTF is, however, unrelated in structure to the nerve growth factor family of neurotrophic factors. Instead, CNTF is distantly related to, and in fact shares receptor components with, a number of hemopoietic cytokines. This review focuses on the biological actions of CNTF, the shared and unique features of the CNTF receptor complex and signaling pathways, and the distribution of CNTF and its receptor during development, in the adult and in response to injury. 相似文献
6.
Repeated treatment with mirtazepine induces brain-derived neurotrophic factor gene expression in rats. 总被引:8,自引:0,他引:8
Recent studies indicate a role of the brain-derived neurotrophic factor (BDNF) in the pathophysiology of depression, as well as in the mechanism of action of antidepressant drugs (ADs). It has been shown that serum BDNF levels are decreased in depressed patients. Moreover, antidepressant treatment increases serum BDNF levels and it is positively correlated with medication response. In addition, repeated administration of ADs induces an increase in rat hippocampal or cortical BDNF gene expression. Since the most potent effect of ADs on BDNF gene expression was found after prolonged treatment, in the present study we investigated the influence of repeated treatment (twice daily for 14 days) of the new AD mirtazapine (5 or 10 mg/kg) on BDNF mRNA level (the Northern blot) in rat hippocampus and cerebral cortex. Imipramine was used as a reference compound. The experiment was carried out on male Wistar rats. The tissue for biochemical assays was collected 24 h after the last doses of mirtazapine and imipramine. We also studied the effect of repeated mirtazapine on the action of the 5-HT2A receptor agonist (+/-)DOI in the behavioral test (head twitches induced by (+/-)DOI) in rats. The obtained results showed that, like imipramine (10 mg/kg), mirtazapine (10 mg/kg) increased BDNF gene expression in both the examined brain regions: in the hippocampus by 24.0 and 26.5%, in the cerebral cortex by 29.9 and 41.5%, respectively, compared with the vehicle-treated control. Neither mirtazapine nor imipramine administered repeatedly at a lower dose (5 mg/kg) significantly changed BDNF mRNA levels in the hippocampus and cerebral cortex. Repeated treatment with mirtazapine (10, but not 5 mg/kg) inhibited the behavioral syndrome induced by (+/-)DOI. This study provides first conclusive evidence that repeated mirtazapine administration increases BDNF mRNA levels; moreover, it indicates that the enhancement of BDNF gene expression may be essential for the clinical effect of mirtazapine. 相似文献
7.
Ciliary neurotrophic factor prevents unweighting-induced functional changes in rat soleus muscle. 总被引:7,自引:0,他引:7
B Fraysse C Guillet C Huchet-Cadiou D C Camerino H Gascan C Léoty 《Journal of applied physiology》2000,88(5):1623-1630
The purpose of the present work was to see whether changes in rat soleus characteristics due to 3 wk of hindlimb suspension could be modified by ciliary neurotrophic factor (CNTF) treatment. Throughout the tail suspension period, the cytokine was delivered by means of an osmotic pump (flow rate 16 microg. kg(-1). h(-1)) implanted under the hindlimb skin. In contrast to extensor digitorum longus, CNTF treatment was able to reduce unweighting-induced atrophy in the soleus. Twitch and 146 mM potassium (K) tensions, measured in small bundles of unloaded soleus, decreased by 48 and 40%, respectively. Moreover, the time to peak tension and the time constant of relaxation of the twitch were 48 and 54% faster, respectively, in unloaded soleus than in normal muscle. On the contrary, twitch and 146 mM K contracture generated in CNTF-treated unloaded and normal soleus were not different. CNTF receptor-alpha mRNA expression increased in extensor digitorum longus and soleus unloaded nontreated muscles but was similar in CNTF-treated unloaded muscles. The present results demonstrate that exogenously provided CNTF could prevent functional changes occurring in soleus innervated muscle subject to unweighting. 相似文献
8.
9.
Ciliary neurotrophic factor prevents neuronal degeneration and promotes low affinity NGF receptor expression in the adult rat CNS. 总被引:7,自引:0,他引:7
Recombinant human ciliary neurotrophic factor (CNTF) was infused for 2 weeks into the lateral ventricle of fimbria-fornix transected adult rats, and its effects were compared with those of purified mouse nerve growth factor (NGF). We provide evidence that CNTF can prevent degeneration and atrophy of almost all injured medial septum neurons (whereas NGF protects only the cholinergic ones). CNTF is also involved in up-regulation of immunostainable low affinity NGF receptor (LNGFR) in cholinergic medial septum and neostriatal neurons and in a population of lateral septum neurons. In contrast to NGF, CNTF did not stimulate choline acetyltransferase in the lesioned septum and normal neostriatum (pointing to different mechanisms for the regulation of choline acetyltransferase and LNGFR), cause hypertrophy of septal or neostriatal cholinergic neurons, or cause sprouting of LNGFR-positive (cholinergic) septal fibers. 相似文献
10.
Steroid hormones and neurotrophic factors exert profound and widespread effects on the developing nervous system, including regulation of the size, connectivity, and survival of neurons. Androgenic control of the survival of motoneurons in the spinal nucleus of the bulbocavernosus (SNB) of rats has been well documented. We previously found that ciliary neurotrophic factor (CNTF) mimics many effects of androgen on the developing SNB. Whether effects of CNTF depend on the presence of a functional androgen receptor was evaluated in the present study. Androgen-insensitive male rats bearing the testicular feminization mutation, Tfm, and female littermates were treated with CNTF or with vehicle alone from embryonic day 22 through postnatal day 3. On postnatal day 4 SNB cell number was elevated in both groups receiving CNTF. Volumes of the bulbocavernosus (BC) and levator ani (LA) muscles, targets of SNB motoneurons, were also markedly increased by CNTF. Since the BC appears to degenerate completely in untreated females, these results indicate that CNTF can delay or prevent muscle fiber death. The relative sparing of muscles and motoneurons did not differ for Tfm males and females, demonstrating that effects of CNTF on the SNB neuromuscular system do not require functional androgen receptors. © 1995 John Wiley & Sons, Inc. 相似文献
11.
睫状神经营养因子对NO引起海马神经元毒性反应的影响 总被引:2,自引:0,他引:2
本研究采用原代培养大鼠海马神经元,观察睫状神经营养因子(ciliary neurotrophic factor,CNTF)对NO引起细胞毒性反应的影响。NO供体硝普钠与S-亚硝基-乙酰青霉胺,NOS底物L-Arg及钙载体ionomycin,均可引起海马神经元存活率下降,LDH漏出增加;提前24h给予不同浓度CNTF,均能提高神经元的存活率,减少LDH漏出,其作用呈剂量依赖性。 相似文献
12.
Repeated co-treatment with imipramine and amantadine induces hippocampal brain-derived neurotrophic factor gene expression in rats. 总被引:2,自引:0,他引:2
The problem of drug-resistant depression indicates a strong need for alternative antidepressant therapies. In our earlier papers we described synergistic, antidepressant-like effects of a combination of imipramine (IMI) and amantadine (AMA) in the forced swimming test in rats, an animal model of depression. Moreover, preliminary clinical data showed that the above-mentioned combination had beneficial effects in treatment-resistant patients. In addition, a number of studies predicted a role of the brain-derived neurotrophic factor (BDNF) in the mechanism of action of antidepressant drugs (ADs). Since the most potent effect of ADs on BDNF gene expression was found after prolonged treatment, in the present study we investigated the influence of repeated treatment with IMI (5 or 10 mg/kg) and AMA (10 mg/kg), given separately or jointly (twice daily for 14 day), on mRNA level (the Northern blot) in the hippocampus and cerebral cortex. The experiment was carried out on male Wistar rats. The tissue for biochemical assays was dissected 24 h after the last dose of IMI and AMA. We also studied the effect of repeated treatment with IMI and AMA on the action of 5-HT(1A)- and 5-HT(2A) receptor agonists (8-OH-DPAT and (+/-)DOI, respectively) in behavioral tests. The obtained results showed that in the hippocampus IMI (10 mg/kg), and in the cerebral cortex IMI (5 and 10 mg/kg) and AMA (10 mg/kg) significantly elevated BDNF mRNA level. Joint administration of IMI (5 or 10 mg/kg) and AMA (10 mg/kg) induced a more potent increase BDNF gene expression in the hippocampus (but not in cerebral cortex) and either inhibited the behavioral syndrome induced by (+/-)DOI or did not change the action of 8-OH-DPAT (compared to treatment with either drug alone). The obtained results suggest that the enhancement of BDNF gene expression may be essential for the therapeutic effect of co-administration of IMI and AMA to drug-resistant depressed patients, and that among other mechanisms, 5-HT(2A) receptors possibly play some role in this effect. 相似文献
13.
14.
Kamla Dutt Yang Cao Ifeoma Ezeonu 《In vitro cellular & developmental biology. Animal》2010,46(7):635-646
Retinitis pigmentosa, age-related macular degeneration, and Parkinson’s disease remain major problems in the field of medicine.
Some of the strategies being explored for treatment include replacement of damaged tissue by transplantation of healthy tissues
or progenitor cells and delivery of neurotrophins to rescue degenerating tissue. One of the neurotrophins with promise is
the ciliary neurotrophic factor (CNTF). In this study, we report the role played by CNTF in retinal cell differentiation and
survival in retinal progenitors. We found that CNTF is a survival factor for multipotential human retinal cells and increased
cell survival by 50%, over a 7-d period, under serum-free conditions, as determined by apoptotic assays (immunohistochemistry
and flow cytometry). This effect is dose dependent with a maximum survival at a CNTF concentration of 20 ng/ml. We also report
that CNTF might be a cell commitment factor, directing the differentiation mainly toward large multipolar cells with ganglionic
and amacrine phenotype. These cells express tyrosine hydroxylase (amacrine cells) as well as, thy 1.1 and neuron-specific
enolase (ganglionic cells). Additionally, there was also an increase in protein kinase C alpha, a protein expressed in rod
and cone bipolars as well as cone photoreceptors and calbindin, a protein expressed in cone photoreceptors and horizontal
cells. In our studies, CNTF doubled the number of cells with ganglionic phenotypes, and basic fibroblast growth factor doubled
the number of cells with photoreceptor phenotype. Additionally, CNTF induced a subset of progenitors to undergo multiple rounds
of cell division before acquiring the large multipolar ganglionic phenotype. Our conclusion is that CNTF could be an agent
that has therapeutic potential and possibly induces differentiation of large multipolar ganglionic phenotype in a subset of
progenitors. 相似文献
15.
Neuronal injury triggers the release of ciliary neurotrophic factor (CNTF), promoting local neuronal repair but producing systemic effects of anorexia and lean body weight loss. Due to the rapid rate of systemic protein loss stimulated by CNTF, we hypothesized involvement of the hepatic ubiquitin-proteasome proteolytic (UPP) pathway in CNTF-induced proteolysis. To assess the role of central CNTF in systemic UPP regulation, we measured hepatic UPP mRNA and proteasome activity in a rat model of neuronal injury and determined alterations induced by intracerebroventricular (ICV) administration of CNTF-neutralizing antibody or additional exogenous CNTF. We also assessed proteolytic parameters and nutritional status by measuring caloric intake, body weight, and protein levels. We produced neuronal injury by implanting a lateral ventricle cannula and giving daily ICV saline bolus injections, which increased hepatic 20S proteasome mRNA and enzymatic activity while reducing caloric intake, body weight, and protein levels compared to controls. Administration of ICV anti-CNTF antibodies (but not control antibodies) prevented these effects. Addition of exogenous CNTF augmented the weight loss along with the increases in 20S proteasome mRNA and proteolytic activity induced by neuronal injury. We conclude that CNTF decreases lean body weight through a combination of appetite inhibition and UPP pathway activation. 相似文献
16.
Ciliary neurotrophic factor blocks rod photoreceptor differentiation from postmitotic precursor cells in vitro 总被引:6,自引:0,他引:6
Matthias Kirsch Steffen Schulz-Key Annette Wiese Sabine Fuhrmann H.-D. Hofmann 《Cell and tissue research》1998,291(2):207-216
The development of photoreceptors in the mammalian retina is thought to be controlled by extrinsic signals. We have shown previously that ciliary neurotrophic factor (CNTF) potently inhibits photoreceptor differentiation in cultures of rat retina. The present study analyzes which developmental processes are affected by CNTF. Rod differentiation as determined by opsin and recoverin immunocytochemistry was effectively blocked by CNTF and leukemia inhibitory factor, but not by other neurotrophic agents tested. CNTF did not influence proliferation, cell death, or survival, and had no effect on the downregulation of nestin immunoreactivity in progenitor cells. Opsin-positive rods could be reverted to an opsin-negative state initially, but became unresponsive to CNTF later. No compensatory increase in the number of other cell types was observed. Application of neutralizing antibodies against CNTF revealed that rod development was partially blocked by an endogenous CNTF-like molecule in control cultures. Our results suggest that CNTF can act as a specific negative regulator of rod differentiation. Its action on photoreceptor precursor cells could serve to synchronize the maturation of photoreceptors, which are born over an extended period of time. Together with other stimulatory signals, CNTF may thus control the temporally and numerically correct integration of photoreceptors into the retinal network. 相似文献
17.
Brain-derived neurotrophic factor stimulates bone/cementum-related protein gene expression in cementoblasts 总被引:1,自引:0,他引:1
Kajiya M Shiba H Fujita T Ouhara K Takeda K Mizuno N Kawaguchi H Kitagawa M Takata T Tsuji K Kurihara H 《The Journal of biological chemistry》2008,283(23):16259-16267
Brain-derived neurotrophic factor (BDNF), recognized as essential in the developing nervous system, is involved in differentiation and proliferation in non-neuronal cells, such as endothelial cells, osteoblasts, and periodontal ligament cells. We have focused on the application of BDNF to the regeneration of periodontal tissue and indicated that BDNF promotes the regeneration of experimentally created periodontal defects. Cementoblasts form cementum, mineralized tissue, which is key to establishing a functional periodontium. The application of BDNF to the regeneration of periodontal tissue requires elucidation of the mechanism by which BDNF regulates the functions of cementoblasts. In this study, we examined how BDNF regulates the mRNA expression of bone/cementum-related proteins (alkaline phosphatase (ALP), osteopontin (OPN), and bone morphogenetic protein-2 (BMP-2)) in cultures of immortalized human cementoblast-like (HCEM) cells. BDNF elevated the mRNA levels of ALP, OPN, and BMP-2 in HCEM cells. Small interfering RNA (siRNA) for TRKB, a high affinity receptor of BDNF, siRNA for ELK-1, which is a downstream target of ERK1/2, and PD98059, an ERK inhibitor, obviated the increase in the mRNA levels. BDNF increased the levels of phosphorylated ERK1/2 and Elk-1, and the blocking of BDNF signaling by treatment with siRNA for TRKB and PD98059 suppressed the phosphorylation of ERK1/2 and Elk-1. Furthermore, BDNF increased the levels of phosphorylated c-Raf, which activates the ERK signaling pathway. These findings provide the first evidence that the TrkB-c-Raf-ERK1/2-Elk-1 signaling pathway is required for the BDNF-induced mRNA expression of ALP, OPN, and BMP-2 in HCEM cells. 相似文献
18.
Maruyama E Ogawa K Endo S Tsujimoto M Hashikawa T Nabetani T Tsugita A 《The international journal of biochemistry & cell biology》2007,39(10):1930-1942
Brain-derived neurotrophic factor (BDNF) is involved in hippocampal functions such as learning and memory and it plays a crucial role in regulating synaptic plasticity. To investigate potential mechanisms by which BDNF participates in neuronal communication through postsynaptic membrane proteins, we generated monoclonal antibodies against the synaptoneurosomal particulate fraction of mouse brain. One of the monoclonal antibodies, termed mAb#27, was found to be useful for analyzing BDNF-induced externalization of synaptoneurosomal membrane proteins of the hippocampus. In dissociated neuronal cultures, BDNF stimulation increased mAb#27 immunoprecipitates of biotin-labeled proteins with apparent masses, 55kDa, 80kDa, 100kDa, 130kDa, 140kDa and 160kDa. The mAb#27 recognition molecules were located in specific hippocampal regions of the brain and at postsynaptic sites in cultured cells. Proteomic studies of the mAb#27 immunocomplex identified newly derived short forms of tenascin R (TNR) as the mAb#27 recognition molecule. Contactin 1, prostaglandin regulatory-like protein and GABA A receptor subunit beta3 were identified as TNR-associated proteins. These proteins were recruited to mAb#27 when BDNF was applied to cells in culture. Each molecules identified in the present study contributes to the postsynaptic plasticity or the active cycle of cellular vesicle membranes. The formation of the TNR complex may serve as an underlying basis for synaptic plasticity in the hippocampus. Our results demonstrate that BDNF plays a role in external molecular dynamics and is likely to regulate synaptic functions such as the enhancement of neuronal excitability through GABAergic neurons. 相似文献
19.
Alexandre C. Rezende Daniele Peroni# rè S. Vieira Fabio Rogerio Rafael L. Talaisys‡ Fabio T. M. Costa‡ Francesco Langone Stephen D. Skaper† Alessandro Negro# 《Journal of neurochemistry》2009,109(6):1680-1690
Ciliary neurotrophic factor (CNTF) is a multifunctional cytokine that can regulate the survival and differentiation of many types of developing and adult neurons. CNTF prevents the degeneration of motor neurons after axotomy and in mouse mutant progressive motor neuronopathy, which has encouraged trials of CNTF for human motor neuron disease. Given systemically, however, CNTF causes severe side effects, including cachexia and a marked immune response, which has limited its clinical application. The present work describes a novel approach for administering recombinant human CNTF (rhCNTF) while conserving neurotrophic activity and avoiding deleterious side effects. rhCNTF was fused to a protein transduction domain derived from the human immunodeficiency virus-1 TAT (transactivator) protein. The resulting fusion protein (TAT-CNTF) crosses the plasma membrane within minutes and displays a nuclear localization. TAT-CNTF was equipotent to rhCNTF in supporting the survival of cultured chicken embryo dorsal root ganglion neurons. Local or subcutaneous administration of TAT-CNTF, like rhCNTF rescued motor neurons from death in neonatal rats subjected to sciatic nerve transection. In contrast to subcutaneous rhCNTF, which caused a 20–30% decrease in body weight in neonatal rats between postnatal days 2 and 7 together with a considerable fat mobilization in brown adipose tissue, TAT-CNTF lacked such side effects. Together, these results indicate that rhCNTF fused with the protein transduction domain/TAT retains neurotrophic activity in the absence of CNTFs cytokine-like side effects and may be a promising candidate for the treatment of motor neuron and other neurodegenerative diseases. 相似文献
20.
Zaldivar D García MC Sánchez JA 《Biochemical and biophysical research communications》2005,338(3):1572-1577
The actions of the ciliary neurotrophic factor (CNTF) were assessed on adult mouse skeletal muscle L-type Ca2+ currents and on Ca2+ release from sarcoplasmic reticulum. Currents were measured with the whole cell patch clamp technique. Ca2+ signals in response to single action potentials were recorded with Fluo3-AM. CNTF (20 ng/ml) reversibly reduced the amplitude of Ca2+ channel currents by 50% within 15 min. In addition, CNTF greatly increased the rate of inactivation during depolarizing pulses and shifted the steady state inactivation curve by -12 mV. The effects of CNTF were mimicked by the PKC activator PMA and prevented by the PKC-inhibitor chelerythrine. In contrast to the effects on the Ca2+ conductance, charge movement and Ca2+ signals remained unaffected by CNTF. These results suggest that CNTF can rapidly decrease muscle Ca2+ channel currents by promoting inactivation, probably through an intracellular PKC-dependent mechanism. 相似文献