Junctophilin 3 expresses in pancreatic beta cells and is required for glucose-stimulated insulin secretion

L, Li; Zf, Pan; Huang, Xianbo; Bw, Wu; T, Li; Mx, Kang; Rs, Ge; Xy, Hu; Yh, Zhang; Liu, Ge; Dy, Zhu; Yl, Wu; Yj, Lou

doi:10.1038/cddis.2016.179

Cited by 34 publications

(33 citation statements)

References 52 publications

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“… 32 , 33 Our previous work has identified that decreased cytoplasm calcium concentration transient amplitude by junctional membrane complex dysfunction reduced the glucose-stimulated insulin secretion of islet β cells. 34 …”

Section: Discussionmentioning

confidence: 99%

“… 43 Moreover, PPAR pathway was correlated with mitochondrial function in islet insulin secretion dysfunction. 34 PPARγ coactivator 1 α PGC-1α regulates HO-1 expression, mitochondrial dynamics, and biogenesis. 44 Our previous work found that PGC-1α inactivation decreased the expression of mitofusin 2, which leaded to damaged mitochondrial function and impaired insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

“… 44 Our previous work found that PGC-1α inactivation decreased the expression of mitofusin 2, which leaded to damaged mitochondrial function and impaired insulin secretion. 34 In summary, we illustrated the key gene pathways and coexpression networks in T2D by applying bioinformatics analysis.…”

Section: Discussionmentioning

confidence: 99%

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Identification of key gene pathways and coexpression networks of islets in human type 2 diabetes

Pan

Yang

et al. 2018

DMSO

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PurposeThe number of people with type 2 diabetes (T2D) is growing rapidly worldwide. Islet β-cell dysfunction and failure are the main causes of T2D pathological processes. The aim of this study was to elucidate the underlying pathways and coexpression networks in T2D islets.Materials and methodsWe analyzed the differentially expressed genes (DEGs) in the data set GSE41762, which contained 57 nondiabetic and 20 diabetic samples, and developed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Protein–protein interaction (PPI) network, the modules from the PPI network, and the gene annotation enrichment of modules were analyzed as well. Moreover, a weighted correlation network analysis (WGCNA) was applied to screen critical gene modules and coexpression networks and explore the biological significance.ResultsWe filtered 957 DEGs in T2D islets. Then GO and KEGG analyses identified that key pathways like inflammatory response, type B pancreatic cell differentiation, and calcium ion-dependent exocytosis were involved in human T2D. Three significant modules were filtered from the PPI network. Ribosome biogenesis, extrinsic apoptotic signaling pathway, and membrane depolarization during action potential were associated with the modules, respectively. Furthermore, coexpression network analysis by WGCNA identified 13 distinct gene modules of T2D islets and revealed four modules, which were strongly correlated with T2D and T2D biomarker hemoglobin A1c (HbA1c). Functional annotation showed that these modules mainly enriched KEGG pathways such as NF-kappa B signaling pathway, tumor necrosis factor signaling pathway, cyclic adenosine monophosphate signaling pathway, and peroxisome proliferators-activated receptor signaling pathway.ConclusionThe results provide potential gene pathways and underlying molecular mechanisms for the prevention, diagnosis, and treatment of T2D.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identification of key gene pathways and coexpression networks of islets in human type 2 diabetes

Pan

Yang

et al. 2018

DMSO

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“…Studies in pancreatic beta cells support such a nonconducting function for Kv2.1 in regulating insulin secretion (92). As this nonconducting role is dependent on Kv2.1 clustering (93) suggests a potential function for Kv2.1 in organizing ER-PM junctions in beta cells, which have been proposed to play an important role in glucose-stimulated insulin secretion (94, 95). Recent studies employing whole exome sequencing have led to identification of encephalopathic epilepsy patients with de novo mutations in the KCNB1 gene that encodes Kv2.1.…”

Section: Discussionmentioning

confidence: 99%

Organizing neuronal ER-PM junctions is a conserved nonconducting function of Kv2 plasma membrane ion channels

Kirmiz

Palacio

Thapa

et al. 2018

Preprint

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27Endoplasmic reticulum (ER) and plasma membrane (PM) form junctions crucial to ion and lipid 28 signaling and homeostasis. The Kv2.1 ion channel is unique among PM proteins in organizing 29 ER-PM junctions. Here, we show that this organizing function is conserved between Kv2 family 30 members that differ in their biophysical properties, modulation and cellular expression. 31Manipulation of actin cytoskeleton surrounding Kv2 ER-PM junctions affects their spatial 32 organization. Kv2-containing ER-PM junctions overlap with those formed by canonical ER-PM 33 tethers. ER-PM junction organization by Kv2 channels is unchanged by point mutations that 34 eliminate ion conduction, but abolished by those that eliminate PM clustering without impacting 35 ion channel function. Kv2.2 is distinct in lacking the reversible modulation of junction organization 36 present in Kv2.1. Brain neurons in Kv2 double knockout mice have altered ER-PM junctions, 37 demonstrating a conserved in vivo function for Kv2 family members distinct from their canonical 38 role as ion-conducting channels shaping neuronal excitability. 39 40. CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/296731 doi: bioRxiv preprint first posted online Apr. 6, 2018; 3 Introduction 41Membrane contacts between the endoplasmic reticulum (ER) and plasma membrane (PM), or 42 ER-PM junctions, are a ubiquitous feature of eukaryotic cells (1-4). These specialized sites at 43 which ER is held in close apposition (10-30 nm) and other excitable and non-excitable cell types. In brain neurons, Kv2 channels are distinct from 63 other Kv channels (17) in being specifically localized to high-density micron sized clusters 64 prominent on the soma, proximal dendrites, and axon initial segment (34-42). Kv2 channels also 65 form such clusters when exogenously expressed in cultured neurons and in heterologous cells 66 . CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/296731 doi: bioRxiv preprint first posted online Apr. 6, 2018; 4 (35, 37, 39, 41-47 at/near RyR clusters in specific neuron types, including hippocampal CA1 pyramidal neurons and 114 layer 6 neocortical neurons (Figure 1). A similar juxtaposition of Kv2.2 and RyR clusters was seen 115 in CHNs (Figure 1). In these classes of neurons, Kv2.2 was often found coclustered with Kv2.1 at 116 these ER-PM junctions (Figure 1). Neurons in each preparation also contained RyR clusters that 117 did not appear to colocalize with Kv2.2 or Kv2.1 (Figure 1). These findings demonstrate that Kv2.2 118 . CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted ...

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“…In addition to the power of genetic analysis in Drosophila , the presence of a single jp gene will prevent masking of the mutant phenotype by other family members, as has been described for murine Jph3 and Jph4 . The restricted tissue specificity of the different JPH genes in mammals is not completely clear cut: JPH1 is required in peripheral nerves in addition to its more studied role in muscle ( Pla-Martin et al, 2015 ); and the neural JPH3 and JPH4 proteins are also required in pancreatic β cells and T cells, respectively ( Li et al, 2016 ; Woo et al, 2016 ). Therefore, an animal model with a single junctophilin gene can help to uncover more ancestral functions.…”

Section: Introductionmentioning

confidence: 99%

The Drosophila junctophilin gene is functionally equivalent to its four mammalian counterparts and is a modifier of a Huntingtin poly-Q expansion and the Notch pathway

Calpena

Amo

Chakraborty

et al. 2018

Disease Models &Amp; Mechanisms

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Members of the Junctophilin (JPH) protein family have emerged as key actors in all excitable cells, with crucial implications for human pathophysiology. In mammals, this family consists of four members (JPH1-JPH4) that are differentially expressed throughout excitable cells. The analysis of knockout mice lacking JPH subtypes has demonstrated their essential contribution to physiological functions in skeletal and cardiac muscles and in neurons. Moreover, mutations in the human JPH2 gene are associated with hypertrophic and dilated cardiomyopathies; mutations in JPH3 are responsible for the neurodegenerative Huntington's disease-like-2 (HDL2), whereas JPH1 acts as a genetic modifier in Charcot–Marie–Tooth 2K peripheral neuropathy. Drosophila melanogaster has a single junctophilin (jp) gene, as is the case in all invertebrates, which might retain equivalent functions of the four homologous JPH genes present in mammalian genomes. Therefore, owing to the lack of putatively redundant genes, a jp Drosophila model could provide an excellent platform to model the Junctophilin-related diseases, to discover the ancestral functions of the JPH proteins and to reveal new pathways. By up- and downregulation of Jp in a tissue-specific manner in Drosophila, we show that altering its levels of expression produces a phenotypic spectrum characterized by muscular deficits, dilated cardiomyopathy and neuronal alterations. Importantly, our study has demonstrated that Jp modifies the neuronal degeneration in a Drosophila model of Huntington's disease, and it has allowed us to uncover an unsuspected functional relationship with the Notch pathway. Therefore, this Drosophila model has revealed new aspects of Junctophilin function that can be relevant for the disease mechanisms of their human counterparts.

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Junctophilin 3 expresses in pancreatic beta cells and is required for glucose-stimulated insulin secretion

Cited by 34 publications

References 52 publications

Identification of key gene pathways and coexpression networks of islets in human type 2 diabetes

Identification of key gene pathways and coexpression networks of islets in human type 2 diabetes

Organizing neuronal ER-PM junctions is a conserved nonconducting function of Kv2 plasma membrane ion channels

The Drosophila junctophilin gene is functionally equivalent to its four mammalian counterparts and is a modifier of a Huntingtin poly-Q expansion and the Notch pathway

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