Lithium estää PI synteesiä inositolitasossa.

PI signalointia pitää yllä PI-PtdOH vaihto Nir2 proteiinin avulla ER-PM kontaktikohdassa

https://www.ncbi.nlm.nih.gov/pubmed/26028218

Dev Cell. 2015 Jun 8;33(5):549-61. doi: 10.1016/j.devcel.2015.04.028. Epub 2015 May 28.

Phosphatidylinositol-Phosphatidic Acid Exchange by Nir2 at ER-PM Contact Sites Maintains Phosphoinositide Signaling Competence. Kim YJ¹, Guzman-Hernandez ML¹, Wisniewski E¹, Balla T².

Sekundaarilähettien  IP3 ja DAG indusoitu  tuotto  vaatii  vakaata PI-muodon  vapautumista synteesikohdiltaan  endoplasmisesta retikulumista (ER)  plasmakalvoon (PM), mikä pitää yllä  tietyn   PIP2  muodon  ( PI-(4,5)P2) pitoisuuksia  solukalvossa. 
Samoin  fosfatidihaponm jota  generoituu plasmakalvossa  diasyyliglyserolista (DAG), pitää päästä takaisin endoplasmiseen retikulumiin  uudelleensyntetisoimisia varten. 

Abstract

• Sustained agonist-induced production of the second messengers InsP3 and diacylglycerol requires steady delivery of phosphatidylinositol (PtdIns) from its site of synthesis in the ER to the plasma membrane (PM) to maintain PtdIns(4,5)P2 levels. 
• Similarly, phosphatidic acid (PtdOH), generated from diacylglycerol in the PM, has to reach the ER for PtdIns resynthesis. 

 Banaanikärpästutkimuksilla on osoitettu , että  Nir2,  oletettu PI molekyylin siirtäjäproteiini,  ei ainoastaan siirrä tätä fosfatidyyli-inositolia (PI)  endoplasmisesta retikulumista (ER)  plasmakalvoon (PM), vaan se siirtää myös fosfatidyylihappoa (PthOH) vastapäiseen suuntaan tässä ER-PM-kontaktikohdassa.
Mutta jos Nir2-proteiinia puuttuu, fosfatidyyli-inositolisynteesis rajoittuu ja lopulta menetetään PLC-entsyymiin kytkeytyneitten reseptorien signalointia.
Nämä tutkimukset paljastavat Nir2-proteiinista ainutlaatuisen piirteen, nimittäin  sen kyvyn toimia erittäin paikallisena lipidien vaihtajana, joka varmistaa PI-syntetisoitumisen  sopivaksi PIP2-molekyylin hyödyntämisen kanssa, niin että solujen signalointi toimii kompetentilla tavalla.

• Here, we show that the Drosophila RdgB homolog, Nir2, a presumed PtdIns transfer protein, not only transfers PtdIns from the ER to the PM but also transfers PtdOH to the opposite direction at ER-PM contact sites. 
•  PtdOH delivery to the ER is impaired in Nir2-depleted cells, leading to limited PtdIns synthesis and ultimately to loss of signaling from phospholipase C-coupled receptors.
•  These studies reveal a unique feature of Nir2, namely its ability to serve as a highly localized lipid exchanger that ensures that PtdIns synthesis is matched with PtdIns(4,5)P2 utilization so that cells maintain their signaling competence. 

Copyright © 2015 Elsevier Inc. All rights reserved.

Free PMC Article

PI- PthOH sykli ja Nir2 funktio (Plasmakalvo- Endoplasminen retikulum-vyöhyke)

http://www.sciencedirect.com/science/article/pii/S1534580715003160

Article

Phosphatidylinositol-Phosphatidic Acid Exchange by Nir2 at ER-PM Contact Sites Maintains Phosphoinositide Signaling Competence

Huomaa, miksi tämä vaihe on hyvin vaurioaltis: Tässä  lipidpuolelle kuuluvat molekyylit PI ja PA, funsamentaaliset pienet  molekyylit kulkevat ilman lipidirakkulasuojaa ja ne tarvitsevat kuljetatjaproteiinin apua ja tässä proteiinisa voi olla jokin geneetinen vika.  Esim ALS-taudissa on kuvassa nkyvässä VAP-B proteiinisa jokin vika niin että se aggrekoituu ja haittaa PI-synteesipuolta.  Tämä on äärettömän fundamentaalinen sykli, jonka pitää toimia.  Pitää katsoa miten tätä voisi kiertää.

 

 

Connexiini kanavat, glukoosi ja inositolijohdannaiset?

https://www.ncbi.nlm.nih.gov/pubmed/?term=connexin++channels%2C+glucose%2C+.inositol

Search results

Items: 3

• Select item 249498451.
• ATP signaling in skeletal muscle: from fiber plasticity to regulation of metabolism.

Casas M, Buvinic S, Jaimovich E.

Exerc Sport Sci Rev. 2014 Jul;42(3):110-6. doi: 10.1249/JES.0000000000000017. Review.

Abstract

Tetanic electrical stimulation releases adenosine triphosphate (ATP) from muscle fibers through pannexin-1 channels in a frequency-dependent manner; extracellular ATP activates signals that ultimately regulate gene expression and is able to increase glucose transport through activation of P2Y receptors, phosphatidylinositol 3-kinase, Akt, and AS160. We hypothesize that this mechanism is an important link between exercise and the regulation of muscle fiber plasticity and metabolism.

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• Select item 219873672.

• Glucose increases intracellular free Ca(2+) in tanycytes via ATP released through connexin 43 hemichannels.

Orellana JA, Sáez PJ, Cortés-Campos C, Elizondo RJ, Shoji KF, Contreras-Duarte S, Figueroa V, Velarde V, Jiang JX, Nualart F, Sáez JC, García MA.

Glia. 2012 Jan;60(1):53-68. doi: 10.1002/glia.21246.

Abstract

The ventromedial hypothalamus is involved in regulating feeding and satiety behavior, and its neurons interact with specialized ependymal-glial cells, termed tanycytes. The latter express glucose-sensing proteins, including glucose transporter 2, glucokinase, and ATP-sensitive K(+) (K(ATP) ) channels, suggesting their involvement in hypothalamic glucosensing. Here, the transduction mechanism involved in the glucose-induced rise of intracellular free Ca(2+) concentration ([Ca(2+) ](i) ) in cultured β-tanycytes was examined. Fura-2AM time-lapse fluorescence images revealed that glucose increases the intracellular Ca(2+) signal in a concentration-dependent manner. Glucose transportation, primarily via glucose transporters, and metabolism via anaerobic glycolysis increased connexin 43 (Cx43) hemichannel activity, evaluated by ethidium uptake and whole cell patch clamp recordings, through a K(ATP) channel-dependent pathway. Consequently, ATP export to the extracellular milieu was enhanced, resulting in activation of purinergic P2Y(1) receptors followed by inositol trisphosphate receptor activation and Ca(2+) release from intracellular stores. The present study identifies the mechanism by which glucose increases [Ca(2+) ](i) in tanycytes. It also establishes that Cx43 hemichannels can be rapidly activated under physiological conditions by the sequential activation of glucosensing proteins in normal tanycytes.

Copyright © 2011 Wiley Periodicals, Inc.

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• Select item 107252203.
• Selective permeability of different connexin channels to the second messenger inositol 1,4,5-trisphosphate.

Niessen H, Harz H, Bedner P, Krämer K, Willecke K.

J Cell Sci. 2000 Apr;113 ( Pt 8):1365-72.

Abstract

Intercellular propagation of signals through connexin32-containing gap junctions is of major importance in physiological processes like nerve activity-dependent glucose mobilization in liver parenchymal cells and enzyme secretion from pancreatic acinar cells.
 In these cells, as in other organs, more than one type of connexin is expressed.

 We hypothesized that different permeabilities towards second messenger molecules could be one of the reasons for connexin diversity. In order to investigate this, we analyzed transmission of inositol 1,4,5-trisphosphate-mediated calcium waves in FURA-2-loaded monolayers of human HeLa cells expressing murine connexin26, -32 or -43. Gap junction-mediated cell coupling in different connexin-transfected HeLa cells was standardized by measuring the spreading of microinjected Mn(2+) that led to local quenching of FURA-2 fluorescence. Microinjection of inositol 1,4,5-trisphosphate into confluently growing HeLa connexin32 transfectants induced propagation of a Ca(2+) wave from the injected cell to neighboring cells that was at least three- to fourfold more efficient than in HeLa Cx26 cells and about 2.5-fold more efficient than in HeLa Cx43 transfectants. Our results support the notion that diffusion of inositol 1,4,5-trisphosphate through connexin32-containing gap junctions is essential for the optimal physiological response, for example by recruiting liver parenchymal cells that contain subthreshold levels of this short lived second messenger.

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Defosforylaatioaspekti: MINPP1 ja paradokaalisesti IP6K defosoryloi. ATP/ADP merkitsevä

https://www.ncbi.nlm.nih.gov/pubmed/24865181/

LÄHDE: Biochem J. 2014 Aug 15;462(1):173-84. doi: 10.1042/BJ20130992.

Discovery of InsP6-kinases as InsP6-dephosphorylating enzymes provides a new mechanism of cytosolic InsP6 degradation driven by the cellular ATP/ADP ratio.

Wundenberg T¹, Grabinski N¹, Lin H¹, Mayr GW¹.

Abstract

InsP6 (inositol hexakisphosphate), the most abundant inositol phosphate in metazoa, is pyrophosphorylated to InsP7 [5PP-InsP5 (diphosphoinositol pentakisphosphate)] by cytosolic and nuclear IP6Ks (InsP6 kinases) and to 1PP-InsP5 by another InsP6/InsP7 kinase family.

 MINPP1 (multiple inositol-polyphosphate phosphatase 1), the only known InsP6 phosphatase, is localized in the ER (endoplasmic reticulum) and lysosome lumina.

 A mechanism of cytosolic InsP6 dephosphorylation has remained enigmatic so far. In the present study, we demonstrated that IP6Ks change their kinase activity towards InsP6 at a decreasing ATP/ADP ratio to an ADP phosphotransferase activity and dephosphorylate InsP6.

 Enantio-selective analysis revealed that Ins(2,3,4,5,6)P5 is the main InsP5 product of the IP6K reaction, whereas the exclusive product of MINPP1 activity is the enantiomer Ins(1,2,4,5,6)P5.

Whereas lentiviral RNAi-based depletion of MINPP1 at falling cellular ATP/ADP ratios had no significant impact on Ins(2,3,4,5,6)P5 production, the use of the selective IP6K inhibitor TNP [N2-(m-trifluorobenzyl),N6-(p-nitrobenzyl)purine] abolished the production of this enatiomer in different types of cells.

 Furthermore, by analysis of rat tissue and human blood samples all (main and minor) dephosphorylation products of InsP6 were detected in vivo.

 In summary, we identified IP6Ks as novel nuclear and cytosolic InsP6- (and InsP5-) dephosphorylating enzymes whose activity is sensitively driven by a decrease in the cellular ATP/ADP ratio, thus suggesting a role for IP6Ks as cellular adenylate energy 'sensors'.

PMID:

24865181

DOI:

10.1042/BJ20130992

[PubMed - indexed for MEDLINE]

IP6K1 geeni, Kr. 3p21.31.

IP6K1 geeni, kromosomi 3p21.31.

IP6K1 inositol hexakisphosphate kinase 1 [ Homo sapiens (human) ]

Yhteenveto: 

 Tämä geeni IP6K1  kuuluu inositolifosfokinaasien perheesen.  Sen koodaama proteiini saattaa vastata inositoli-6- fosfaatin ( fytiinin, IP6) konvertoitumista  difosfo-inositoli-penta-cis-fosfaatiksi  IP7/ PP-IP5. Se saattaa  myös konvertoida  1,3,4,5,6- pentakisfosfaatin (IP5)  muotoon PP-IP4, joka on IP6 variantti.  On kuvattu alternatiivisesti pleissautunut transkriptivariantti.

Gene ID: 9807, updated on 19-Jan-2017

Summary

Official Symbol

IP6K1 provided by HGNC

Official Full Name

inositol hexakisphosphate kinase 1provided by HGNC

Primary source

HGNC:HGNC:18360

See related

Ensembl:ENSG00000176095 MIM:606991; Vega:OTTHUMG00000158197

Gene type

protein coding

RefSeq status

REVIEWED

Organism

Homo sapiens

Lineage

Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo

Also known as

PiUS; IHPK1

Summary

This gene encodes a member of the inositol phosphokinase family. The encoded protein may be responsible for the conversion of inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). It may also convert 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jun 2011]

LISÄTIETOA artikkeleissa

Related articles in PubMed

1. Discovery of InsP6-kinases as InsP6-dephosphorylating enzymes provides a new mechanism of cytosolic InsP6 degradation driven by the cellular ATP/ADP ratio. Wundenberg T, et al. Biochem J, 2014 Aug 15. PMID 24865181
2. Characterization of a selective inhibitor of inositol hexakisphosphate kinases: use in defining biological roles and metabolic relationships of inositol pyrophosphates. Padmanabhan U, et al. J Biol Chem, 2009 Apr 17. PMID 19208622, Free PMC Article
3. The IHPK1 gene is disrupted at the 3p21.31 breakpoint of t(3;9) in a family with type 2 diabetes mellitus. Kamimura J, et al. J Hum Genet, 2004. PMID 15221640
4. PiUS (Pi uptake stimulator) is an inositol hexakisphosphate kinase. Schell MJ, et al. FEBS Lett, 1999 Nov 19. PMID 10567691
5. Localization of PiUS, a stimulator of cellular phosphate uptake to human chromosome 3p21.3. White KE, et al. Somat Cell Mol Genet, 1998 Jan. PMID 9776982
   

See all (26) citations in PubMed
See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into Functions

What's a GeneRIF?

1. IP6K1 is a novel CRL4 subunit that transduces UV signals to mediate disassembly of the CRL4-CSN complex, thereby regulating nucleotide excision repair and cell death.
2. we identified IP6Ks as novel nuclear and cytosolic InsP6- (and InsP5-) dephosphorylating enzymes whose activity is sensitively driven by a decrease in the cellular ATP/ADP ratio
3. FGF2-signaling involves the inositol polyphosphate cascade, including inositol hexakisphosphate kinase (IP6K), and demonstrate that IP6K1,2 regulates Runx2 and osteoblast gene expression.
4. Observational study of gene-disease association. (HuGE Navigator)
5. Results report the characterization of an inhibitor, N(2)-(m-(trifluoromethy)lbenzyl) N(6)-(p-nitrobenzyl)purine (TNP), selective for inositol hexakisphosphate kinases.
6. IHPK1 gene is disrupted at the 3p21.31 breakpoint of t(3;9) in a family with type 2 diabetes mellitus
   Muistiin 24.1. 2017
   

IP6K2 geeni, Kr. 3p21.31.

IP6K2 geeni, kr. 3.

IP6K2 fosforyloi inositolihexakisfosfaattia IP7- muotoon, jolloin se on IP5-pyrofosfaattia . Sitä merkitään joko IP7:ksi.
Mahdollisesti se voi konvertoida myös IP5 muodon, jossa on inositolirenkaan fosfaatit asemissa 1,3,4,5,6, muotoon PP-Ins4, difosfoinositol-tetrakisfosfaatti , jolloin se on IP4- pyrofosfaattia. Ja vaikuttaa kasvusupressiota ja IFN-beetan apoptoottisia aktiivisuuksia joissain ovariaalisyövissä.
diphosphoinositol pentakisphosphate (InsP7/PP-InsP5)
Lähde: https://www.ncbi.nlm.nih.gov/gene/51447

P6K2 inositol hexakisphosphate kinase 2 [ Homo sapiens (human) ]

Gene ID: 51447, updated on 6-Dec-2016

Summary

Official Symbol

IP6K2provided by HGNC

Official Full Name

inositol hexakisphosphate kinase 2 provided by HGNC

Primary source

HGNC:HGNC:17313

See related

Ensembl:ENSG00000068745 MIM:606992; Vega:OTTHUMG00000133543

Gene type

protein coding

RefSeq status

REVIEWED

Organism

Homo sapiens

Lineage

Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo

Also known as

PIUS; IHPK2

Summary

This gene encodes a protein that belongs to the inositol phosphokinase (IPK) family. This protein is likely responsible for the conversion of inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5).

It may also convert 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4 and affect the growth suppressive and apoptotic activities of interferon-beta in some ovarian cancers. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

Tästä pyrofosfaattia tekevästä entsyymistä IP6K2 on useita artikkeleita.

Related articles in PubMed

1. Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2. Chakraborty A, et al. Proc Natl Acad Sci U S A, 2011 Feb 8. PMID 21262846, Free PMC Article
2. Inositol hexakisphosphate kinase-2, a physiologic mediator of cell death. Nagata E, et al. J Biol Chem, 2005 Jan 14. PMID 15533939
3. Inositol hexakisphosphate kinase 2 sensitizes ovarian carcinoma cells to multiple cancer therapeutics. Morrison BH, et al. Oncogene, 2002 Mar 14. PMID 11896621, Free PMC Article
4. IP6K structure and the molecular determinants of catalytic specificity in an inositol phosphate kinase family. Wang H, et al. Nat Commun, 2014 Jun 24. PMID 24956979, Free PMC Article
5. Inositol hexakisphosphate kinase 2 mediates growth suppressive and apoptotic effects of interferon-beta in ovarian carcinoma cells. Morrison BH, et al. J Biol Chem, 2001 Jul 6. PMID 11337497, Free PMC Article
   

See all (33) citations in PubMed
See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. An alpha-helical pair and a rare, two-turn 310 helix, that together form a substrate-binding pocket of IP6K2.
2. FGF2-signaling involves the inositol polyphosphate cascade, including inositol hexakisphosphate kinase (IP6K), and demonstrate that IP6K1,2 regulates Runx2 and osteoblast gene expression.
3. Genetic polymorphisms in IP6K2 gene is associated with autoimmune disease.
4. Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2.
5. Gene disruption of IP6K2 in colorectal cancer cells selectively impairs p53-mediated apoptosis, instead favoring cell-cycle arrest. IP6K2 acts by binding directly to p53 and decreasing expression of proarrest gene targets
6. InsP6K2 is a physiologic mediator of cell death
7. IHPK2-TRAF2 binding leads to attenuation of TAK1- and NF-kappaB-mediated signaling and is partially responsible for the apoptotic activity of IHPK2.
8. IHPK2 over expression enhances sensitivity of ovarian carcinoma cells to radiation, IFN-beta, caspase 8 and DR4
   

Submit: New GeneRIF Correction

Muistiin inositolihexakisfosfaattikinaasista
24.1. 2016