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L type Ca2+ channel blockers prevent oxaliplatin-induced cold hyperalgesia and TRPM8 overexpression in rats
Takehiro Kawashiri, Nobuaki Egashira, Kentaro Kurobe, Kuniaki Tsutsumi, Yuji Yamashita, Soichiro Ushio, Takahisa Yano, Ryozo Oishi
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-7
Abstract: Cold hyperalgesia was assessed by the acetone test. Oxaliplatin (4 mg/kg), sodium oxalate (1.3 mg/kg) or vehicle was injected i.p. on days 1 and 2. Ca2+ (diltiazem, nifedipine and ethosuximide) and Na+ (mexiletine) channel blockers were administered p.o. simultaneously with oxaliplatin or oxalate on days 1 and 2.Oxaliplatin (4 mg/kg) induced cold hyperalgesia and increased in the transient receptor potential melastatin 8 (TRPM8) mRNA levels in the dorsal root ganglia (DRG). Furthermore, oxalate (1.3 mg/kg) significantly induced the increase in TRPM8 protein in the DRG. Treatment with oxaliplatin and oxalate (500 μM for each) also increased the TRPM8 mRNA levels and induced Ca2+ influx and nuclear factor of activated T-cell (NFAT) nuclear translocation in cultured DRG cells. These changes induced by oxalate were inhibited by nifedipine, diltiazem and mexiletine. Interestingly, co-administration with nifedipine, diltiazem or mexiletine prevented the oxaliplatin-induced cold hyperalgesia and increase in the TRPM8 mRNA levels in the DRG.These data suggest that the L type Ca2+ channels/NFAT/TRPM8 pathway is a downstream mediator for oxaliplatin-induced cold hyperalgesia, and that Ca2+ channel blockers have prophylactic potential for acute neuropathy.Oxaliplatin, a platinum-based chemotherapeutic agent, is widely used for treatment of colorectal cancer. However, oxaliplatin frequently causes severe acute and chronic peripheral neuropathies. Acute neuropathy is peculiar to oxaliplatin and includes acral paresthesias enhanced by exposure to cold [1-4]; the acute neuropathy is not attributed to morphological damage to the nerve [5,6]. On the other hand, the chronic neuropathy is characterized by loss of sensory and motor function after long-term oxaliplatin treatment, and it is similar to cisplatin-induced neurological symptoms [4]. Recently, we reported that repeated administration of oxaliplatin induced cold hyperalgesia in the early phase and mechanical allodynia in the l
Involvement of spinal NR2B-containing NMDA receptors in oxaliplatin-induced mechanical allodynia in rats
Yuki Mihara, Nobuaki Egashira, Hikaru Sada, Takehiro Kawashiri, Soichiro Ushio, Takahisa Yano, Hiroaki Ikesue, Ryozo Oishi
Molecular Pain , 2011, DOI: 10.1186/1744-8069-7-8
Abstract: Repeated administration of oxaliplatin (4 mg/kg, i.p., twice a week) caused mechanical allodynia in the fourth week, which was reversed by intrathecal injection of MK-801 (10 nmol) and memantine (1 μmol), NMDA receptor antagonists. Similarly, selective NR2B antagonists Ro25-6981 (300 nmol, i.t.) and ifenprodil (50 mg/kg, p.o.) significantly attenuated the oxaliplatin-induced pain behavior. In addition, the expression of NR2B protein and mRNA in the rat spinal cord was increased by oxaliplatin on Day 25 (late phase) but not on Day 5 (early phase). Moreover, we examined the involvement of nitric oxide synthase (NOS) as a downstream target of NMDA receptor. L-NAME, a non-selective NOS inhibitor, and 7-nitroindazole, a neuronal NOS (nNOS) inhibitor, significantly suppressed the oxaliplatin-induced pain behavior. The intensity of NADPH diaphorase staining, a histochemical marker for NOS, in the superficial layer of spinal dorsal horn was obviously increased by oxaliplatin, and this increased intensity was reversed by intrathecal injection of Ro25-6981.These results indicated that spinal NR2B-containing NMDA receptors are involved in the oxaliplatin-induced mechanical allodynia.Glutamate is a major excitatory transmitter in the spinal cord and N-methyl-D-aspartate (NMDA) receptors are known to be involved in the painful neuropathy [1,2]. The NMDA receptor antagonist inhibits the pain hypersensitivity in chronic constriction injury (CCI) model. Moreover, the expression of spinal NR2B-containing NMDA receptors is increased with the pain hypersensitivity induced by CCI or chronic compression of the dorsal root ganglia (CCD) [3-6]. Selective NR2B antagonists inhibit mechanical allodynia without causing motor dysfunction in CCI, CCD and spinal nerve-ligated (SNL) neuropathic models [5-8]. In addition, the NR2B subunits are localized to the superficial dorsal horn of the spinal cord [7,9], suggesting a possible involvement in pain transmission. Thus, the NR2B-containing NMDA re
A Dynamic Model of Interactions of Ca2+, Calmodulin, and Catalytic Subunits of Ca2+/Calmodulin-Dependent Protein Kinase II  [PDF]
Shirley Pepke ,Tamara Kinzer-Ursem ,Stefan Mihalas,Mary B. Kennedy
PLOS Computational Biology , 2010, DOI: 10.1371/journal.pcbi.1000675
Abstract: During the acquisition of memories, influx of Ca2+ into the postsynaptic spine through the pores of activated N-methyl-d-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca2+ influx during the first few seconds of activity is interpreted within the Ca2+-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity, including Ca2+/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bind up to 4 Ca2+ ions. As a first step toward clarifying how the Ca2+-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca2+, calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca2+ play a significant role in activation of CaMKII in the physiological regime, supporting the notion that processing of Ca2+ signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca2+ is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca2+ transients arises from the kinetics of interaction of fluctuating Ca2+ with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning.
Ca2+/Calmodulin and Presynaptic Short-Term Plasticity  [PDF]
Sumiko Mochida
ISRN Neurology , 2011, DOI: 10.5402/2011/919043
Abstract: Synaptic efficacy is remodeled by neuronal firing activity at the presynaptic terminal. Presynaptic activity-dependent changes in transmitter release induce postsynaptic plasticity, including morphological change in spine, gene transcription, and protein synthesis and trafficking. The presynaptic transmitter release is triggered and regulated by Ca2+, which enters through voltage-gated Ca2+ (CaV) channels and diffuses into the presynaptic terminal accompanying action potential firings. Residual Ca2+ is sensed by Ca2+-binding proteins, among other potential actions, it mediates time- and space-dependent synaptic facilitation and depression via effects on CaV2 channel gating and vesicle replenishment in the readily releasable pool (RRP). Calmodulin, a Ca2+-sensor protein with an EF-hand motif that binds Ca2+, interacts with CaV2 channels and autoreceptors in modulation of SNARE-mediated exocytosis. 1. Introduction For memory formation in a neuronal circuit, the primary function of presynaptic terminals is the firing activity-dependent release of neurotransmitters and subsequent recycling of their carrier synaptic vesicles, processes which critically depend on ATP and Ca2+. Presynaptic firing of action potentials activates voltage-gated Ca2+??(CaV) channels, and Ca2+ entry initiates release of neurotransmitters. Ca2+??dependence on fast neurotransmitter release is thought to be conferred by the synaptotagmin, a family of Ca2+ sensors that interact with SNAREs [1]. Synaptotagmin 1 and 2 are synaptic vesicle proteins with tandem C2 domains that bind Ca2+ and ensure the synchronization of Ca2+-dependent exocytosis with the presynaptic action potential [2–5]. Neuronal firing activity also controls other protein functions and dynamically remodels synaptic efficacy. Ca2+-binding proteins sensing residual Ca2+, which accumulates locally in the presynaptic terminal during trains of action potentials, may act as potential effectors for these reactions. Considerable evidence supports a role for calmodulin (CaM), another family of Ca2+ sensors with an EF hand motif that binds Ca2+, in modulation of SNARE-mediated exocytosis [6, 7] and endocytosis [8, 9]. Targets of CaM include multiple proteins implicated in exocytosis (e.g., Ca2+ channels [10], Ca2+/ CaM kinase II [11], rab3 [12], and Munc13 [13]), and endocytosis (e.g., calcinulin [14]). Another Ca2+-binding protein with an EF hand motif, parvalbumin, acts as a mobile presynaptic Ca2+ buffer that accelerates withdrawal of residual Ca2+ and decay of short-term facilitation in the calyx of held [15] and GABAergic
Immunohistochemical localization of Ca2+/calmodulin-dependent kinase in tobacco
Wannian Yang,Shuping Liang,Yingtang Lu
Chinese Science Bulletin , 2001, DOI: 10.1007/BF03187175
Abstract: The existence of Ca2+/calmodulin-dependent kinase (CaM kinase, CaMK) in tobacco is verified immunologically and its distribution in different tissues of tobacco is studied. It has been demonstrated that CaMK is mainly distributed in early developing anthers, developing ovules and embryos, lateral root primordium, apical meristem and leaf primordium of buds and mesophyll cells and developing vascular bundles of leaves. There is enormous CaM kinase distributed in leaf epidermis fair cells and guard cells of stomas too. Little kinase is found in mature stem or root cells. The distribution properties of CaM kinase in tobacco are consistent with those of CaM, suggesting that there exists the Ca2+ signal transduction pathway mediated by CaM kinase in tobacco and it plays an important role in the plant growth and development.
RyRCa2+ Leak Limits Cardiac Ca2+ Window Current Overcoming the Tonic Effect of Calmodulin in Mice  [PDF]
María Fernández-Velasco,Gema Ruiz-Hurtado,Angélica Rueda,Patricia Neco,Martha Mercado-Morales,Carmen Delgado,Carlo Napolitano,Silvia G. Priori,Sylvain Richard,Ana María Gómez,Jean-Pierre Benitah
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020863
Abstract: Ca2+ mediates the functional coupling between L-type Ca2+ channel (LTCC) and sarcoplasmic reticulum (SR) Ca2+ release channel (ryanodine receptor, RyR), participating in key pathophysiological processes. This crosstalk manifests as the orthograde Ca2+-induced Ca2+-release (CICR) mechanism triggered by Ca2+ influx, but also as the retrograde Ca2+-dependent inactivation (CDI) of LTCC, which depends on both Ca2+ permeating through the LTCC itself and on SR Ca2+ release through the RyR. This latter effect has been suggested to rely on local rather than global Ca2+ signaling, which might parallel the nanodomain control of CDI carried out through calmodulin (CaM). Analyzing the CICR in catecholaminergic polymorphic ventricular tachycardia (CPVT) mice as a model of RyR-generated Ca2+ leak, we evidence here that increased occurrence of the discrete local SR Ca2+ releases through the RyRs (Ca2+ sparks) causea depolarizing shift in activation and a hyperpolarizing shift inisochronic inactivation of cardiac LTCC current resulting in the reduction of window current. Both increasing fast [Ca2+]i buffer capacity or depleting SR Ca2+ store blunted these changes, which could be reproduced in WT cells by RyRCa2+ leak induced with Ryanodol and CaM inhibition.Our results unveiled a new paradigm for CaM-dependent effect on LTCC gating and further the nanodomain Ca2+ control of LTCC, emphasizing the importance of spatio-temporal relationships between Ca2+ signals and CaM function.
Surface Dynamics in Allosteric Regulation of Protein-Protein Interactions: Modulation of Calmodulin Functions by Ca2+  [PDF]
Yosef Y. Kuttner,Tal Nagar,Stanislav Engel
PLOS Computational Biology , 2013, DOI: 10.1371/journal.pcbi.1003028
Abstract: Knowledge of the structural basis of protein-protein interactions (PPI) is of fundamental importance for understanding the organization and functioning of biological networks and advancing the design of therapeutics which target PPI. Allosteric modulators play an important role in regulating such interactions by binding at site(s) orthogonal to the complex interface and altering the protein's propensity for complex formation. In this work, we apply an approach recently developed by us for analyzing protein surfaces based on steered molecular dynamics simulation (SMD) to the study of the dynamic properties of functionally distinct conformations of a model protein, calmodulin (CaM), whose ability to interact with target proteins is regulated by the presence of the allosteric modulator Ca2+. Calmodulin is a regulatory protein that acts as an intracellular Ca2+ sensor to control a wide variety of cellular processes. We demonstrate that SMD analysis is capable of pinpointing CaM surfaces implicated in the recognition of both the allosteric modulator Ca2+ and target proteins. Our analysis of changes in the dynamic properties of the CaM backbone elicited by Ca2+ binding yielded new insights into the molecular mechanism of allosteric regulation of CaM-target interactions.
The Ca2+ Influence on Calmodulin Unfolding Pathway: A Steered Molecular Dynamics Simulation Study  [PDF]
Yong Zhang,Jizhong Lou
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049013
Abstract: The force-induced unfolding of calmodulin (CaM) was investigated at atomistic details with steered molecular dynamics. The two isolated CaM domains as well as the full-length CaM were simulated in N-C-terminal pulling scheme, and the isolated N-lobe of CaM was studied specially in two other pulling schemes to test the effect of pulling direction and compare with relevant experiments. Both Ca2+-loaded CaM and Ca2+-free CaM were considered in order to define the Ca2+ influence to the CaM unfolding. The results reveal that the Ca2+ significantly affects the stability and unfolding behaviors of both the isolated CaM domains and the full-length CaM. In Ca2+-loaded CaM, N-terminal domain unfolds in priori to the C-terminal domain. But in Ca2+-free CaM, the unfolding order changes, and C-terminal domain unfolds first. The force-extension curves of CaM unfolding indicate that the major unfolding barrier comes from conquering the interaction of two EF-hand motifs in both N- and C- terminal domains. Our results provide the atomistic-level insights in the force-induced CaM unfolding and explain the observation in recent AFM experiments.
Ca2+-mediated activation of ERK in hepatocytes by norepinephrine and prostaglandin F2α: role of calmodulin and src kinases
?yvind Melien, Laila S Nilssen, Olav F Dajani, Kristin Sand, Jens-Gustav Iversen, Dagny L Sandnes, Thoralf Christoffersen
BMC Cell Biology , 2002, DOI: 10.1186/1471-2121-3-5
Abstract: Pretreatment of the cells with the Ca2+ chelators BAPTA-AM or EGTA, as well as the Ca2+ influx inhibitor gadolinium, resulted in a partial decrease of the ERK response. Furthermore, the calmodulin antagonists W-7, trifluoperazine, and J-8 markedly decreased ERK activation. Pretreatment with KN-93, an inhibitor of the multifunctional Ca2+/calmodulin-dependent protein kinase, had no effect on ERK activation. The Src kinase inhibitors PP1 and PP2 partially diminished the ERK responses elicited by both norepinephrine and PGF2α.The present data indicate that Ca2+ is involved in ERK activation induced by hormones acting on G protein-coupled receptors in hepatocytes, and suggest that calmodulin and Src kinases might play a role in these signaling pathways.The extracellular signal regulated kinases ERK1 (p44mapk) and ERK2 (p42mapk) are activated in response to stimulation of receptor tyrosine kinases (RTKs) as well as heptahelical G protein coupled receptors (GPCR) and transmit signals which regulate cell differentiation and growth [1-3]. The molecular steps involved in signaling from GPCRs to ERK are incompletely understood. Data obtained in various cell systems have provided evidence in support of several signaling pathways including protein kinase C (PKC) [4], Ca2+-mediated mechanisms [5-12], and transactivation of receptor tyrosine kinases [13,14]. In hepatocytes several hormones, including vasopressin, angiotensin II, norepinephrine, and PGF2α, that bind to GPCRs activate ERK [15-17]. The mechanisms mediating the ERK activation by GPCR agonists are not clarified; there is evidence that protein kinase C is involved [15,18], but a role for Ca2+ also appears likely, since all the agents above activate phospholipase C and elevate intracellular Ca2+ in hepatocytes [19,20]. Furthermore, agents that elevate intracellular Ca2+ through mechanisms bypassing receptors have been found to activate ERK [15,21]. However, agonist-stimulated phospholipase C activity is rapidly down-reg
Lobe Specific Ca2+-Calmodulin Nano-Domain in Neuronal Spines: A Single Molecule Level Analysis  [PDF]
Yoshihisa Kubota ,M. Neal Waxham
PLOS Computational Biology , 2010, DOI: 10.1371/journal.pcbi.1000987
Abstract: Calmodulin (CaM) is a ubiquitous Ca2+ buffer and second messenger that affects cellular function as diverse as cardiac excitability, synaptic plasticity, and gene transcription. In CA1 pyramidal neurons, CaM regulates two opposing Ca2+-dependent processes that underlie memory formation: long-term potentiation (LTP) and long-term depression (LTD). Induction of LTP and LTD require activation of Ca2+-CaM-dependent enzymes: Ca2+/CaM-dependent kinase II (CaMKII) and calcineurin, respectively. Yet, it remains unclear as to how Ca2+ and CaM produce these two opposing effects, LTP and LTD. CaM binds 4 Ca2+ ions: two in its N-terminal lobe and two in its C-terminal lobe. Experimental studies have shown that the N- and C-terminal lobes of CaM have different binding kinetics toward Ca2+ and its downstream targets. This may suggest that each lobe of CaM differentially responds to Ca2+ signal patterns. Here, we use a novel event-driven particle-based Monte Carlo simulation and statistical point pattern analysis to explore the spatial and temporal dynamics of lobe-specific Ca2+-CaM interaction at the single molecule level. We show that the N-lobe of CaM, but not the C-lobe, exhibits a nano-scale domain of activation that is highly sensitive to the location of Ca2+ channels, and to the microscopic injection rate of Ca2+ ions. We also demonstrate that Ca2+ saturation takes place via two different pathways depending on the Ca2+ injection rate, one dominated by the N-terminal lobe, and the other one by the C-terminal lobe. Taken together, these results suggest that the two lobes of CaM function as distinct Ca2+ sensors that can differentially transduce Ca2+ influx to downstream targets. We discuss a possible role of the N-terminal lobe-specific Ca2+-CaM nano-domain in CaMKII activation required for the induction of synaptic plasticity.
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