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Enhanced store-operated Ca2+ signal of small intestinal smooth muscle cells accelerates small bowel transit speed in type 1 diabetic mouse

Enhanced store-operated Ca2+ signal of small intestinal smoo...

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第十一届全国钙信号和细胞功能研讨会

作者： Fang Dai Jizheng Guo Tian Jiang Dacheng Sang Ying Hu Juan Du Xianming Xia Qiu Zhang Bing Shen Department of Endocrinology the First Affiliated Hospital of Anhui Medical University Department of Physiology Anhui Medical University Department of Gastroenterology and Hepatology the Fourth Affiliated Hospital of Anhui Medical University

The underlying mechanism of diabetic enteropathy, a common complication of type 1 diabetes, remains unclear. Store-operated Ca entry(SOCE) is a ubiquitous type of Ca influx involved in various cellular functions. Here, we show that SOCE-related stromal interaction molecule 1(STIM1) and Orai1 participate in inappropriate cellular Ca homeostasis, augmenting agonistinduced small intestinal smooth muscle contraction and small bowel transit speed in a mouse model of type 1 diabetes. We used small interfering(si)RNA to suppress STIM1 and Orai1 proteins, and employed intracellular Ca, small intestinal contraction and intestinal transit speed measurement to investigate the functional change. We found that SOCE activity and Orai1 and STIM1 expression levels of small intestinal smooth muscle were significantly increased in cells cultured in high glucose medium or in diabetic mice. Gastrointestinal transit speed and SOCE-mediated contractions were markedly increased in diabetic mice;however, knocking down Orai1 or STIM1 with si RNA rescued both alterations. The Orai1–large conductance Ca-activated K+(BKCa) channel interaction was decreased in diabetic mice, and suppressing Orai1 expression or inhibiting the BKCa channel reduced agonist-induced small intestinal contractions. We concluded that the increased SOCE caused by excessive STIM1 and Orai1 expression and decreased Orai1–BKCa interaction augmented small intestinal smooth muscle contraction and accelerated small bowel transit speed in diabetic mice. This finding demonstrates a pathological role for SOCE in diabetic enteropathy and provides a potential therapeutic target for diabetic enteropathy.

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Functional Orai1 Dimers Assemble to Form Hexameric Channels

Functional Orai1 Dimers Assemble to Form Hexameric Channels

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第十一届全国钙信号和细胞功能研讨会

作者： Xiangyu Cai Yandong Zhou Xianming Wang Robert M.Nwokonko Natalia A Loktionova Donald L.Gill Department of Cellular and Molecular Physiology Pennsylvania State University College of Medicine The Milton S.Hershey Medical Center

The multimeric assembly of the CRAC channel has remained a contentious issue despite strong crystallographic evidence of a hexameric structure for both Drosophila and human Orai1. Recent studies suggested concatemeric tetramers of Orai1 mediate authentic CRAC current whereas equivalent hexameric concatemers form only non-selective cation channels. We expressed concatenated human Orai1 constructs with intervening 36-aa linkers. We compared expression and function of C-terminally td Tomato-tagged monomeric, dimeric, trimeric, tetrameric, pentameric and hexameric concatemers of human Orai1 in HEK cells in which Orai1 was knocked out using CRSPR technology and cells stably expressed STIM1-YFP. All constructs were observed to be exclusively PM-localized. The Orai1 monomer, dimer, trimer, tetramer, pentamer and hexamer constructs all gave rise to the same level of store-operated Ca2+ entry, and exhibited authentic CRAC channel activity with similar inward rectification and reversal potential. In experiments substituting wt-Orai1 subunits with pore-inactive E106 A mutant subunits, we observed that the initial two N-terminal units of tetrameric Orai1 concatemers are crucial for channel activity. The remaining two C-terminal residues in tetramers were inconsequential for function. In hexamers, the position of inactive mutants in the concatemer are not specific. Substitution with a single E106 A mutant monomer in the hexamer had similar effect in reducing channel function at each position. Substitution with two E106 A residues at the first N-terminal positions in the hexamer resulted in no channel function. Substitution with two E106 A residues elsewhere in the hexamer, resulted in approximately 50% of channel the wildtype hexamer. We interpret these results to reveal that hexamers, not tetramers, are likely the true functional Orai1 channel unit. Tetrameric concatemers appear to feed dimers into a hexameric structure, with the two remaining Cterminal residues outside the hex

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Cooperative regulation of Cav1.2 channels by intracellular Mg2+, calmodulin, and the channel C-terminal domain

Cooperative regulation of Cav1.2 channels by intracellular M...

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第十一届全国钙信号和细胞功能研讨会

作者： Zhuo Li Chen Sichong Meimi Zhao Liying Hao Department of Pharmaceutical Toxicology School of Pharmacy China Medical University

L-type Ca currents conducted by Cav1.2 channels initiate excitation-contraction coupling in cardiac myocytes. Intracellular Mg（Mgi） inhibits the ionic current of Cav1.2 channels. Because Mgi is altered in ischemia and heart failure, its regulation of Cav1.2 channels is important in understanding cardiac pathophysiology. Here, we studied the effects of Mgi on the single channel currents of L-type Ca channels in guinea pig ventricular myocytes by adopting the inside-out configuration of the patch clamp technique. We confirmed that increased Mgi inhibits calmodulin（Ca M）-induced channel activity in dose-dependent manner. When Mgi was increased to 100 m M, the Ca M-induced channel acitivity decreased to 20 ± 1% of the control activity in cell-attached mode. The Cav1.2 channels have been shown to demonstrate a model behavior in the gating kinetics, which has been characterized and collated as three different gating modes, 0, 1, and 2. We found the decreased channel activity caused by increased Mgi was dependent on channel gating kinetics, especially mode 2 gating. To investigate whether increased Mgi inhibits the channel activity through the modulation of Ca M binding with Cav1.2 channels, we examined the binding of Ca M with the C-terminal tails（CT1） of Cav1.2 channels using the pull-down assay method. Our results showed that increased Mgi substantially reduced the Ca M binding capability to CT1. Our results demonstrate cooperative regulation of Cav1.2 channel activity by Mgi, Ca M and CT1, and suggest that increased Mgi inhibits the channel activity through Ca M binding to CT1.

关键词： and the channel C-terminal domain Cooperative regulation of Cav1.2 channels by intracellular Mg calmodulin domain

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Calcium/Calmodulin-dependent Protein Kinase Ⅱ Inhibition Induces Hyperexcitability by Abnormal Interactions between Calmodulin and Na V1.2 in a Rat Model of Genetic Epilepsy

Calcium/Calmodulin-dependent Protein Kinase Ⅱ Inhibition In...

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第十一届全国钙信号和细胞功能研讨会

作者： Feng Guo Huiqian Wang Xiaoxue Xu Zhi Li Liying Hao Department of Pharmaceutical Toxicology School of Pharmacy China Medical University

Abnormal calcium/calmodulin(CaM)-dependent kinase Ⅱ(CaMKII) changes have been shown to be involved in many epileptic models, however, the exact mechanisms underlying CaMKII inhibition in epilepsy is unkown. Additionally, the relationship between the Ca M/Ca MKII pathway and voltage-gated sodium channels(VGSCs) is not well understood in epilepsy. KN93, a specific CaMKII inhibitor, was applied by lateral ventricular injection both in normal Wistar and tremor(TRM) rats, a rat model of genetic epilepsy. Ca MKII inhibition resulted in abnormal interactions and co-localizations between VGSC subtype NaV1.2 and CaM in the hippocampus of TRM rats as detected by co-immunoprecipitation and double-labeling immunofluorescence. Additionally, elevated [Ca]i was observed in TRM rats folloiwing Ca MKII inhibition. CaM bound to the C-terminal ‘IQ’ motif of NaV1.2 in a concentration-and Ca-dependent manner as observed by pull-down assay. Electrophysiological patch-clamp technique demonstrated that VGSC activity in cultured hippocampal neurons is more sensitive to Ca M modulation at higher [Ca]. Moreover, neuronal excitability, measured by EEG, was enhanced in both the Wistar and TRM rats following Ca MKII inhibition. Furthermore, using the Morris water maze test we observed that Ca MKII inhibition induced learning and memory impairments associated with down-regulation of cA MP-response element-binding protein(CREB) signaling in both Wistar and TRM rats. For the first time, our data support an in vivo model of epilepsy whereby Ca MKII inhibition produces hyperexcitability associated with an abnormal interaction between VGSC and Ca M, suggesting that loss of Ca MKII activity might be a central factor in epileptogenesis.

关键词： Calmodulin Calcium/calmodulin（Ca M）-dependent kinase II Epilepsy Voltagegated sodium channels

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Calcium/Calmodulin-dependent Protein Kinase Ⅱ Inhibition Induces Neuronal Death in a Rat Model of Genetic Epilepsy

Calcium/Calmodulin-dependent Protein Kinase Ⅱ Inhibition In...

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第十一届全国钙信号和细胞功能研讨会

作者： Zhi Li Huiqian Wang Xiaoxue Xu Jianing Li Dongyi Zhao Liying Hao Feng Guo Department of Pharmaceutical Toxicology School of Pharmacy China Medical University

Abnormal Calcium/calmodulin(Ca M)-dependent kinase Ⅱ(Ca MKII) change has been involved in many epileptic models. However, the mechanisms basing on Ca MKII inhibition in epilepsy is still unknown. In this study, we applied KN93, a specific Ca MKII inhibitor, by lateral ventricular injection both in normal Wistar and tremor(TRM) rats, a rat model of genetic epilepsy. Ca MKII inhibition resulted a significant increase in TUNEL staining of neurons in TRM rats DG region and activated caspase-3 labeling was increased both in normal rats and TRM rats hippocampus after the application of KN93, respectively. Additionally, the expression level of Neu N in both control Wistar rats and TRM rats after the application of KN93 were significantly decreased compared to those observed in both control Wistar rats and TRM rats, respectively. Interestingly, the expression level of GFAP in both control Wistar rats and TRM rats after the application of KN93 were significantly increased compared to those observed in control Wistar rats and TRM rats, respectively. Moreover, the expression of p-ERK in control Wistar rats and TRM rats hippocampus after the application of KN93 were significantly decreased compared to those observed in control Wistar rats and TRM rats. Additionally, the expression of p-JNK in control Wistar rats and TRM rats hippocampus after the application of KN93 were significantly increased compared to those observed in control Wistar rats and TRM rats, respectively. Thus, we found the neurotoxicity but not neuroprotection induced by KN93 both in normal rats and tremor rat hippocampus. For the first time, our data support a model in vivo whereby the inhibition of Ca MKII produces cell death in epilepsy associated with dysregulated MAPK signaling.

关键词： Calmodulin Calcium/calmodulin(Ca M)-dependent kinase II Epilepsy KN93 MAPK

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Excitation-Coupled Calcium Entry in fast and slow twitch muscles

Excitation-Coupled Calcium Entry in fast and slow twitch mus...

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第十一届全国钙信号和细胞功能研讨会

作者： B.Mosca L.Bergamelli J.Eckhard S.Treves F.Zorzato Department of Life Sciences and Biotechnology University of Ferrara Dept.of Anesthesiology University Hospital Basel

Skeletal muscle dihydropyridine receptors(Cav1.1) act as Ca channels and voltage sensors to initiate muscle contraction by activating ryanodine receptors, the Ca release channels of the sarcoplasmic reticulum. Cav1.1 channel activity is enhanced by a retrograde stimulatory signal delivered by the ryanodine receptor. JP45 is a junctional sarcoplasmic reticulum membrane protein interacting with Cav1.1 and the Ca storage protein calsequestrin(CASQ). We hypothesize that JP45 and CASQ form a signalling pathway modulating Cav1.1 channel activity. We tested this hypothesis in a variety of mouse models, including WT, JP45 KO, CASQ1 KO, CASQ2 KO, JP45/CASQ1 double KO(DKO1), JP45/CASQ2 double KO(DKO2) and JP45/CASQ1/CASQ2 triple KO(TKO). Our results show that Ca transient in flexor digitorum brevis(FDB) muscle from DKO1, DKO2 and TKO fibresevoked by tetanic stimulation in fibres, result from massive Ca influx via La3+-and nifedipine-sensitive calcium channels(1, 2). Calcium entry enahnced by ablation of both JP45/CASQ1 and JP45/CASQ2 complexes supports tetanic force development infast EDL-and slow-twitch Soleus muscles(1,2). We also found that CASQs interact with JP45 at [Ca] similar to those present in the lumen of the sarcoplasmic reticulum at rest, while [Ca] similar to those present in the SR lumen after depolarisation-induced calcium release cause the dissociation of JP45 from CASQs. We conclude that the complex JP45/CASQs is a negative regulator of excitation-coupled calcium entry, and that tetanic force development in fast and slow twitch muscles is supported by the dynamic interaction between JP45 and CASQs

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The effect of Ca MK II and CIP on the binding of calmodulin to cardiac Cav1.2 channel

The effect of Ca MK II and CIP on the binding of calmodulin ...

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第十一届全国钙信号和细胞功能研讨会

作者： Jingyang Su Liting Lyu Jianwei Mao Guigui Wei Dongxue Shao Meimi Zhao Feng Guo Huiyuan HU Xuefei Sun Guangyu Jiao Rui Feng Hao Liying Department of Pharmaceutical Toxicology School of Pharmacy China Medical University Respiratory Department and Intensive Care Unit Shengjing Hospital of China Medical University

In the present study, the roles of Ca/Ca M dependent protein kinase II（Ca MKII） and Calf Intestinal Alkaline Phosphatase（CIP） on the binding of calmodulin（Ca M） to cardiac Cav1.2 channel were examined by pull-down assay method. We examined the binding of Ca M to cardiac Cav1.2 fragments after treated by Ca MKII and CIP. The experiments showed that the Cav1.2 C-terminal fragment CT1 still has the ability to bind with Ca M after treatments at different Ca concentration([Ca]) from ≈ free to 2 m M. The binding effects of Ca M to CT1 were increased by CaM KII phosphorylation with CaM-concentration dependent manner, and the binding effects of Ca M to CT1 were decreased by CIP dephosphorylation with Ca Mconcentration dependent manner. To further find the key regions in CT1 for Ca MKII and CIP regulation, we examined the binding effect of Ca M to IQ after Ca MKII and CIP treatment. The results showed that the binding effect were increased after Ca MKII treatment, and were decreased after CIP treatment in 2 mM, 10μM Ca, in additon, the effect were Ca Mconcentration dependent manner. The data imply that at higher Ca, Ca M can easily bind to CT1 after Ca MKII phosphorylation, and the binding effect was easily inhibited after CIP dephosphorylation. Furthermore, the IQ motif might be the important region for Ca MKII and CIP to mediate CaM binding.

关键词： calmodulin Ca2+/Ca M dependent protein kinase II L-type calcium channel phosphorylation

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TRPC6 and NCX1 complex regulates TGFβ-mediated cellular behavior of human hepatocellular carcinoma

TRPC6 and NCX1 complex regulates TGFβ-mediated cellular beh...

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第十一届全国钙信号和细胞功能研讨会

作者： Jingyu Xu Yuan Yang Yixia Jiang Guorong Wen Bei Ji Hai Jin Xuemei Liu Rui Xie Biguang Tuo Department of Gastroenterology Affiliated Hospital Zunyi Medical College Digestive Disease Institute of Guizhou Province Research Center of Medicine and Biology Zunyi Medical College

Backgrounds & Aims: Transforming growth factor β（TGFβ） plays important role in the formation, progression, and metastasis of hepatocellular carcinoma（HCC）. However, the cellular and molecular mechanisms of TGFβ action on HCC are not completely understood. Ca signaling controls various cellular processes relevant to the development and progression of tumor. In this study, we investigated the role of canonical transient receptor potential channel 6（TRPC6） and Na/Ca exchanger 1（NCX1） in TGFβ-mediated cellular behavior of human HCC. Methods: The experiments were performed in native human HCC tissues and human HCC cell lines. The xenograft model of human HCC was established in nude mice. Results: TGFβ stimulated intracellular Ca([Ca]i) increases in Hep G2 and Huh7 cells. The pharmacological inhibition and genetic suppression of both TRPC6 and NCX1 inhibited the TGFβ-induced [Ca]i changes. The expressions of both TRPC6 and NCX1 were markedly increased in native human HCC tissues. TGFβ upregulated TRPC6 and NCX1 expressions and induced the interaction of TRPC6 and NCX1 in Hep G2 and Huh7 cells. TGFβ promoted the migration and invasion of the HCC cells and induced their mesenchymal phenotype. The pharmacological inhibition and genetic suppression of both TRPC6 and NCX1 and the chelation of intracellular Ca inhibited the action of the TGFβ. Conclusion: TRPC6 and NCX1 complex-mediated Ca signaling regulates TGFβ-mediated cellular behavior of human HCC, which reveals the role of TRPC6 and NCX1 molecular complex in tumor and a novel TGFβ signal pathway and implicates that TRPC6 and NCX1 may be potential targets for HCC therapy.

关键词： TGF TRPC6 and NCX1 complex regulates TGF mediated cellular behavior of human hepatocellular carcinoma HCC NCX

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From contraction to gene expression: nanojunctions of the sarcoplasmic reticulum deliver function-specific calcium signals

From contraction to gene expression: nanojunctions of the sa...

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第十一届全国钙信号和细胞功能研讨会

作者： A.Mark Evans Centre for Integrative Physiology College of Medicine and Veterinary Medicine Hugh Robson Building University of Edinburgh

Calcium signals determine smooth muscle contraction and the switch from acontractile to a migratory-proliferative phenotype(s), which requires changes in geneexpression. However the mechanism by which different calcium signals select for these processes is enigmatic. We have shown that SERCA2 b and Ry R1 arepreferentially targeted to the sarcoplasmic reticulum(SR) proximal to the plasmamembrane(PM;Clark et al., 2010), i.e., to the superficial buffer barrier formed by PM-SR nanojunctions(van Breemen et al., 2013), and support vasodilation. Here, increases in SERCA2 b activity may remove calcium from the deeper cytoplasm to the superficial SR, from which calcium sparks may be released into the PM-SR junction via Ry R1 to activate PM resident BKCa channels, driving hyperpolarisation(Boittin et al., 2003), removal of calcium from the cell by forward mode NCX activity and ultimately vasodilation(Boittin et al., 2003;Clark et al., 2010). In marked contrast, SERCA2 a is entirely restricted to the deep, perinuclear SR(Clark et al.,2010) and may function to recycle calcium into this subcompartment in support of vasoconstriction(Dipp & Evans, 2001;Kinnear et al., 2004;Clark et al., 2010). Importantly, Ry R3 is also preferentially targeted to the perinuclear SR and associated lysosome-SR nanojunctions(Kinnear et al., 2004, Kinnear et al., 2008), while the distribution of Ry R2 is more widespread and extends from this region to the wider cell(Kinnear et al., 2008;Clark et al., 2010). We therefore proposed that perinuclear clusters of Ry R3 may act as an initiation site for propagating calcium waves and contraction(Dipp & Evans, 2001;Kinnear et al., 2008). Thereafter, by calcium-induced calcium release, Ry R2 may carry propagating calcium waves away from perinuclear clusters of Ry R3 and across the myofilaments to enhance myocyte contraction(Kinnear et al., 2008;Clark et al., 2010). A third subtype of SERCA pump in PASMCs, namely SERCA1, and Ry R1 preferentially lines invaginati

关键词： SERCA From contraction to gene expression nanojunctions of the sarcoplasmic reticulum deliver function-specific calcium signals

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Leaky ryanodine receptor in atrial fibrillation

Leaky ryanodine receptor in atrial fibrillation

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第十一届全国钙信号和细胞功能研讨会

作者： Wenjun Xie Gaetano Santuli Steven Reiken Andrew R.Marks Xi'an Jiaotong University Columbia Unviersity

Atrial fibrillation(AF) is the most common cardiac arrhythmia with high morbidity and mortality in elder, however the mechanism(s) causing AF remain poorly understood and therapy is suboptimal. Abnormal intracellular calcium signals have been recently proposed to play important roles in the pathogenesis of AF. In atrial myocytes, the main intracellular calcium release channel on the sarcoplasmic reticulum(SR) is type 2 ryanodine receptor(Ry R2). Here, we examined AF in mice models harboring dysfunctional Ry R2 mutations, including Ry R2-R2474 S, a human catecholaminergic polymorphic ventricular tachycardia(CPVT) mutation, and Ry R2-S2808 D that mimic chronic PKA phosphorylation of Ry R2. Both mice displayed increased AF susceptibility(70% in R2474S(7/10), 68% in S2808D(13/19), compared to ≤10% in WT control) accompanied by increased diastolic SR calcium leak(2.2 and 2.0 folds calcium sparks frequencies in Ry R2-R2474 S and Ry R2-S2808 D compared to WT control) in atrial myocytes. Further, we found Ry R2 in these mice atria were oxidized. We examined the atrial mitochondria, one of the main intracellular ROS sources, to find increased mitochondrial oxidative stress and mitochondrial dysmorphology in these mutation mice. Importantly, genetic inhibition of mitochondrial ROS production reduced Ry R2 oxidation and SR calcium leak. Moreover, pharmacological inhibition of Ry R2 calcium leak restored atrial mitochondrial morphology and function. Both approaches prevented AF. Our results demonstrated that alterations of Ry R2 inducing intracellular calcium leak trigger a vicious cycle, in which SR calcium leak in atrial myocytes impairs mitochondrial function leading to an increase in ROS production, thereby promoting Ry R2 oxidation and further calcium leak in the development of AF. Targeting this previously unrecognized mechanism could be useful in developing effective interventions to prevent and treat AF.

关键词： ryanodine Leaky ryanodine receptor in atrial fibrillation

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