What Do You Know About IP6/IP-6/inositol Hexaphosphate/phytate/phytic Acid?

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Altered Ca2 + signaling in cancer cells: Proto-oncogenes and tumor suppressors targeting IP3 receptors
2013


Abstract

Proto-oncogenes and tumor suppressors critically control cell-fate decisions like cell survival, adaptation and death. These processes are regulated by Ca2 + signals arising from the endoplasmic reticulum, which at distinct sites is in close proximity to the mitochondria. These organelles are linked by different mechanisms, including Ca2 +-transport mechanisms involving the inositol 1,4,5-trisphosphate receptor (IP3R) and the voltage-dependent anion channel (VDAC). The amount of Ca2 + transfer from the endoplasmic reticulum to mitochondria determines the susceptibility of cells to apoptotic stimuli. Suppressing the transfer of Ca2 + from the endoplasmic reticulum to the mitochondria increases the apoptotic resistance of cells and may decrease the cellular responsiveness to apoptotic signaling in response to cellular damage or alterations. This can result in the survival, growth and proliferation of cells with oncogenic features. Clearly, proper maintenance of endoplasmic reticulum Ca2 + homeostasis and dynamics including its links with the mitochondrial network is essential to detect and eliminate altered cells with oncogenic features through the apoptotic pathway. Proto-oncogenes and tumor suppressors exploit the central role of Ca2 +signaling by targeting the IP3R. There are an increasing number of reports showing that activation of proto-oncogenes or inactivation of tumor suppressors directly affects IP3R function and endoplasmic reticulum Ca2 + homeostasis, thereby decreasing mitochondrial Ca2 + uptake and mitochondrial outer membrane permeabilization. In this review, we provide an overview of the current knowledge on the proto-oncogenes and tumor suppressors identified as IP3R-regulatory proteins and how they affect endoplasmic reticulum Ca2 +homeostasis and dynamics.

Source: Altered Ca2 + signaling in cancer cells: Proto-oncogenes and tumor suppressors targeting IP3 receptors - ScienceDirect
 
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Also see this, which also contains what you spoke of, concerning calmodulin and its mechanism, and how IP3 mediates terminal differentiation. It's a page from a book called Molecular Basis of Breast Cancer: Prevention and treatment:

Molecular Basis of Breast Cancer
 
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What are Inositol Triphosphate (IP3) and Inositol Hexaphosphate (IP6) Molecules?
Inositol has six carbon atoms that are capable of binding phosphate molecules; when all six carbons are occupied by six phosphate groups the compound is called IP6. When only three of the carbon groups are bound by phosphate it is called IP3. Inositol hexaphosphate (IP6) is a component of fiber primarily found in whole grains and legumes. Studies indicate that the cancer protective effects of high fiber diets are partly due to the presence of higher levels of IP6 in the fiber. Supplementation with purified IP6 and the correct amounts of inositol offers several advantages over dietary sources of these compounds, including enhanced bioavailability and absorption. IP6 has strong antioxidant and immune enhancing effects as well as exerting a number of interesting anticancer actions. IP6 taken together with inositol inhibits the ability of cancer cells to multiply. The combination of IP6 with inositol was originally discovered by Dr Shamsuddin M.D., Ph.D., from the University of Maryland, USA. When combined with IP6, inositol dramatically increases the anticancer and immune enhancing effects of IP6. Although IP6 is gaining media attention, it is really IP3 that is doing all the work. Dr Shamsuddin discovered that when properly combined with inositol, IP6 forms two molecules of inositol triphosphate (IP3) in the body. IP3 plays an important role inside the cells of our bodies. It basically functions as an on/off switch for human cancers according to studies in cell cultures. When IP3 levels are low (as in cancer cells), the cells replicate out of control. That basically is what occurs in cancer. When cancer cells are bathed in a broth of IP3, they literally turn themselves off. This action reflects the central role that IP3 plays in controlling key cell functions, including replication and the communication between cells. Dr Shamsuddin has discovered the correct ratio of IP6 and inositol to ensure the formation of IP3 within the body. Based on extensive studies in animals and cell cultures, the combination of IP6 and inositol exerts anticancer effects against virtually all types of cancers including cancers of the breast, prostate, lung, skin, colon and brain as well as lymphomas and leukemia. IP6 reduces the manufacture of new DNA in cancer cells but does not exert the same inhibition in normal cells. IP6 is superior in this way to chemotherapy agents because it helps cancer cells to function normally without damaging healthy cells.

Source: Inositol, IP3 and IP6
 
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Calcium signaling in apoptosis:

A description of the role calcium plays in apoptosis, focusing on the endoplasmic reticulum and mitochondria.
Apoptosis is a highly regulated mechanism of cell death, essential in development and tissue homeostasis. Apoptosis can occur via the extrinsic pathway, with ligand binding to death receptors on the cell surface, or via an internal pathway involving the mitochondria.

Learn more about apoptosis pathways

Both pathways converge at the activation of caspases, which cleave cytoskeletal proteins and nuclear lamins, and promote DNA degradation.

It is clear that subtle changes in Ca2+ concentration can regulate and trigger apoptosis. Here we describe how Ca2+ is important in the intrinsic apoptosis pathway by promoting the release of pro-apoptotic factors from mitochondria and subsequent caspase activation.

Ca2+ movement between the endoplasmic reticulum (ER) and mitochondria
The ER is an important Ca2+ storage organelle, maintaining a concentration of 0.1–1 mM, compared with 100 nM in the cytosol and mitochondrial matrix (Hajnóczky et al., 2003). Release of this stored Ca2+ and subsequent uptake by the mitochondria is a mechanism that can trigger apoptosis.

Inositol trisphosphate (IP3) receptor-mediated Ca2+ release from the ER, transmits Ca2+ to surrounding mitochondria using local interactions between ER and mitochondria. This release can be triggered by ER stress when the capacity of the ER to fold proteins properly is compromised (Orrenius et al., 2003).

Alternatively, in a positive feedback mechanism proposed by Boehning et al.(2003), a small amount of cytochrome c is released from mitochondria upon an apoptotic stimulus, which subsequently binds IP3 receptors on the surface or ER, triggering calcium release.

Ca2+ accumulation in the mitochondria leads to mitochondrial membrane permeabilization by stimulating the opening of the mitochondrial permeability transition pore (mPTP, Orrenius et al., 2003). Opening of the mPTP results in the release of pro-apoptotic factors, in particular cytochrome c.

The role of BCL-2 proteins in Ca2+-mediated apoptosis
The BCL-2 family of proteins is central to the regulation of apoptosis. They can be divided into those that are anti-apoptotic such as BCL-2 and BCL-xL, and those that are pro-apoptotic such as BAX, BAK and BAD, among many others.

BCL-2 proteins are associated with mitochondria, where they are involved in altering membrane permeability and regulating the release of cytochrome c and other pro-apoptotic factors (Chipuk et al., 2010). However, they are also associated with the ER, where there is evidence that they have a role in regulating Ca2+ fluxes across the membrane.

Expression of the anti-apoptotic BCL-2 protein reduces Ca2+ release from the ER and subsequent uptake by the mitochondria, either by lowering ER Ca2+load (Pinton et al., 2000; Foyouzi et al., 2000), or by interacting with IP3 receptor directly, reducing the probability of the channel opening (Rong et al., 2008).

Pro-apoptotic members of the BCL-2 protein family have also been implicated in Ca2+-dependent apoptosis. BAX and BAK control Ca2+homeostasis in the ER and mitochondria and promote mitochondrial calcium uptake (Scorrano et al., 2003; Nutt et al., 2002). Additionally, BAD and tBID have been shown to sensitize the mitochondria to Ca2+ making them more susceptible to Ca2+ release from the ER (Roy et al., 2009; Csordás et al., 2002).

Source: Calcium signaling in apoptosis | Abcam
 
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I will have to digest and study this literature first, before coming to new conclusions, but it is sure very interesting so far. What do you think of this Ca2+ signaling with IP3, @Travis? Also see the red underlined sentence in the post above.
 
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Quick link on the IP3 calcium signaling in the heart, (PDF file. Very good read):

https://www.springer.com/cda/conten...7611462-c1.pdf?SGWID=0-0-45-940544-p173890014

"The cellular role for inositol 1,4,5- trisphosphate receptors (IP3 R) has remained elusive. However, there is great and growing interest in cardiac IP3 signaling due to the known importance of several IP3 -inducing agonists (e.g., endothelin, angiotensin II, and norepinephrine) in both hypertrophy and HF [28]. While agonist-induced IP3 -dependent Ca2+ release is readily observed in most tissues, the role of IP3 Rs in cardiac tissue is less clear. The role played by IP3 Rs has yet to be convincingly demonstrated in the normal heart. However, there are suggestions that it may lead to amplification of Ca2+ signals from the RyR2 or be independently activated through several diverse pathways that lead to the generation of IP3 [29]. This second calcium release channel in the sarcoplasmic reticulum may play a role in normal excitation–contraction coupling. There are also suggestions that the importance of IP3 Rs can change significantly during normal aging [30]. This implies that these other calcium release channels may have an increased importance during the development of HF.

Calcium Sensitivity

Myocardial contraction is initiated when Ca2+ binds to a specific site on cardiac troponin C [31]. This 12-residue EF-hand loop contains six residues that coordinate Ca2+ binding and six residues that do not appear to influence Ca2+ binding directly [32]. Structural changes in troponin C affect its calcium sensitivity [32]. Ca2+ binding affinity controls contractile force and changes in many types of diseases. Troponin C is part of a troponin complex that together with tropomyosin affects the interaction between actin and myosin leading to the development of myocardial contraction [33, 34]. The interaction between troponin C and calcium is the critical final step of calcium induced control of myocardial contractility. Stretch also affects calcium sensitivity and force development [35]. This is part of the explanation for the Frank–Starling mechanism [36], which may be affected by stretch activated calcium channels. In addition to troponin C, there are several other calcium binding proteins that affect myocardial contractility [37], including calpains and calcium dependent protein kinases [38–41]. These various calcium binding proteins regulate the force of myocardial contraction in the normal heart. Mutations in troponin C have been associated with the development of HF [34], and changes in calcium sensitivity of troponin may be a potentially useful treatment for HF [42, 43]. As the heart progresses into failure significant reductions in calcium sensitivity occur [33, 44]. Furthermore, decreased phosphorylation level of troponin C occurs in HF [45], and this may be contributory to the decreased contractile function observed in the failing heart [33]. Agents that stabilize troponin C may prove useful. Several reports have claimed that the increased sensitivity of troponin to calcium observed in the failing heart is due to changes in phosphorylation of troponin I [46]. Several mutations in troponin isoforms have been associated with HF [34]. The ability of the heart to respond to wall stress is also depressed [3]. Other myocardial calcium-binding proteins may also be useful targets for gene therapy in HF [37, 41]."

Maybe this study can shed some light on the safety of use of IP6 + inositol, creating 2 IP3 molecules?

The study also contains 2 illustrations of cardiac myocytes and the entry and exit of calcium in them.

 
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Hmmm...

Inositol Triphosphate does not release Ca2+ from permeabilized cardiac myocytes and sarcoplasmic reticulum

1985

The possibility that mosltol 1.4,5-tnsphosphate (IPJ may act as a Ca Z+-moblhzmg second messenger m cardiac muscle m a manner analogous to Its actions m other cell types has been examined usmg saponm-permeablhzed myocytes and isolated cardiac sarcoplasmic reticulum Myocytes permeabilized in the presence of MgATP2- sequestered Ca 2+ to a level of about 200 nM, similar to the cytosohc free Ca”+ concentration of intact cells, but addition of IP, was ineffective m causmg Ca2+ release from intracellular stores Similarly. IP, (up to 50 PM) was unable to mhlblt Ca2+ uptake or cause Ca2+ release from Isolated cdmne cardiac sarcoplasmic reticulum vesicles m the presence of either EGTA or sodmm vanadate These results indicate that IP, IS unlikely to mediate moblhzatlon of mtracellular Ca2+ stores m myocardidl cells

Inositol trisphosphate does not release Ca2+ from permeabilized cardiac myocytes and sarcoplasmic reticulum - ScienceDirect

This is confusing... What do you think?
 

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OK @Travis , I have a bottle of Cell Forte IP-6 Inositol staring at me. Should I take it?
 

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OK @Travis , I have a bottle of Cell Forte IP-6 Inositol staring at me. Should I take it?

Not the entire bottle at once! but I think over time it should help eliminate excessive iron and prevent hydroxyl radical formation.
 

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I will have to digest and study this literature first, before coming to new conclusions, but it is sure very interesting so far. What do you think of this Ca2+ signaling with IP3, @Travis? Also see the red underlined sentence in the post above.

I don't think the 'IP₃ receptor' does as supposed, and believe that calcium influx is better explained by the physical interaction of IP₃ with Ca²⁺.

Luttrell, B. "The biological relevance of the binding of calcium ions by inositol phosphates." Journal of Biological Chemistry (1993)
 
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I don't think the 'IP₃ receptor' does as supposed, and believe that calcium influx is better explained by the physical interaction of IP₃ with Ca²⁺.

Luttrell, B. "The biological relevance of the binding of calcium ions by inositol phosphates." Journal of Biological Chemistry (1993)
"One important question facing cell biologists is whether the high ER [Ca2+] has a function beyond warehousing Ca2+. Is protein sorting conducted in this strange environment, or are there separate and dynamically rearranged ER pools? Do high free and buffered concentrations of Ca2+ in the ER and Golgi network contribute to condensation of proteins observed in protein sorting, and if so, what happens to protein processing when stores are emptied?"


"Ca2+ gradients within cells have been proposed to initiate cell migration, exocytosis, lymphocyte killer cell activity, acid secretion, transcellular ion transport, neurotransmitter release, gap junction regulation, and numerous other functions (Tsien and Tsien, 1990). The most complex wave patterns, exhibiting hotspots and spherical, spiral, and planar waves, were demonstrated in Xenopus oocytes (Lechleiter et al., 1991b). There appears to be insufficient space within a single 10-20 I~m mammalian cell for such complex patterns, but similar patterns have been observed in larger cardiac cells and in networks of astrocytes and glia. Ca2+ signals between cells have also been identified in brain and epithelial function. Our understanding of the brain may be radically changed by observations of Ca2+ waves spreading across astrocytes and exciting overlying neuronal cells, either through gap junctions (Nedergaard, 1994) or via glutamate neurotransmisson between astrocytes and neurons (Parpura et al., 1994)."

Calcium Signaling, David E. Clapham, Department of Pharmacology, Mayo Foundation, Rochester, Cell, Vol. 80, 259-268, January 27, 1995 https://www.cell.com/cell/pdf/0092-8674(95)90408-5.pdf?_returnURL=https://linkinghub.elsevier.com/retrieve/pii/0092867495904085?showall=true
 
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"Calcium (Ca2+) is a primary regulator of physiological function for all cells. Its role as an intracellular messenger was evident from the nineteenth century when the English physiologist Sydney Ringer found that Ca2+ stimulates cardiac muscle contraction (86). Since that time an incredibe diversity of cellular functions has been shown to be triggered by Ca2+. Ca2+ is well suited as an intracellular messenger because in resting cells free Ca2+ levels are only about 0.1 µM, ten thousandfolds lower than extracellular levels. In neurons and muscles (i.e. excitable cells), hormones and neurotransmitters take advantage of this chemical gradient by triggering the opening of voltage-dependent Ca2+ channels in the plasma membrane, thereby producing an influx of extracellular Ca2+. At least three subtypes of such voltage-dependent Ca2+ channels appear to exist. one of these, the L channel, is potently influenced by Ca2+ antagonist drugs such as dihydropyridine, which have been employed as ligands that permit the isolation of the L channel receptor protein and its subsequent molecular cloning [(102, see reference (9) for recent brie review]. However, many cellular functions known to be dependent upon Ca2+ can be triggered by aproppriate agonists even when"

Inositol 1,4,5-Trisphosphate-Activated Calcium Channels, Christopher D. Ferris, Solomon H. Snyder, Annual Review of Physiology, Volume 54, 1992 Department of Neuroscience, Pharmacology and Molecular Sciences, Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine (full text is behind a paywall)

https://www.annualreviews.org/doi/abs/10.1146/annurev.ph.54.030192.002345
 
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Selective down-regulation of IP3receptor subtypes by caspases and calpain during TNF α -induced apoptosis of human T-lymphoma cells

Abstract

There are at least three types of inositol 1,4,5-trisphosphate receptor (IP3R) [IP3-gated Ca2+channels], which are expressed in different cell types and mammalian tissues. In this study, we have identified three IP3R subtypes in human Jurkat T-lymphoma cells. All three subtypes have a molecular mass of about 260 kDa, and display Ca2+channel properties in an IP3-dependent manner. We have also demonstrated that TNFα promotes the activity of different proteases (e.g. caspase-8, caspase-3 and calpain), alters the TCR-mediated Ca2+response and subsequently induces apoptosis in Jurkat cells. During the first 6 h of incubation with TNFα, several IP3R subtype-related changes occur (e.g. proteolysis of IP3R subtypes, inhibition of IP3binding and impairment of IP3-mediated Ca2+flux) concomitantly with an elevation of protease (caspase-8, caspase-3 and calpain) activity. Furthermore, the caspase inhibitor, Z-VAD-fmk, significantly reduces TNFα-mediated perturbation of IP3R1 and IP3R2 (but not IP3R3) function; whereas the calpain inhibitor I, ALLN, is capable of blocking the inhibitory effect of TNFα on IP3R3 function. These findings suggest that IP3R1 and IP3R2 serve as cellular substrates for caspases, and IP3R3 is a substrate for calpain. We propose that the selective down-regulation of IP3R subtype-mediated Ca2+function by caspase-dependent and calpain-sensitive mechanisms may be responsible for the early onset of the apoptotic signal by TNFα in human T-cells.

F. Diaz, L.Y.W. Bourguignon, Department of Cell Biology and Anatomy, University of Miami Medical School, Miami, USA, Cell Calcium Volume 27, Issue 6, June 2000 Pages 315-328

Source: Selective down-regulation of IP3receptor subtypes by caspases and calpain during TNF α -induced apoptosis of human T-lymphoma cells - ScienceDirect
 
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"IV. Function of IP3 receptor

1. Ca2+ channel


As evidenced by the ligand binding data, the purified IP3 receptor clearly satisfies the properties of a physiological receptor for IP3. That both IP3 receptor and Ca2+ release channel reside in the same protein was first suggested by single channel analyses using planer lipid bilayers reconstituted with microsomal proteins from aortic smooth muscle (74). The experiments with purified type 1 IP3 receptor incorporated into reconstituted vesicles (83) or planer lipid bilayers (66, 84) further provided evidence that both IP3 receptor and Ca2+ channel are integrated in the same molecule. Thus, the IP3 receptor is analogous to other ligand-gated ion channels except for its primary association with intracellular membranes. Our current knowledge about the Ca2+ channel properties of IP3 receptor has been provided mainly from single channel analyses using planer lipid bilayers reconstituted with crude microsomal proteins from cerebellum (for a review, see ref. 8). The channel properties of type 2 and type 3 IP3 receptors are largely unknown. The Ca2+ channel of the cerebellar IP3 receptor (type 1) is activated by IP3, the only known physiological activator, with an EC50 of around 0.2 pM: it can maximally activate the channel at 1 uM. The IP3 receptor, when activated, can conduct all four alkaline earth cations with conductances in the order of Ba2+ > Sr2+ > Ca2+ > Mg2+. The ryanodine receptor can also conduct these divalent cat ions in this order, although conductances are approximately twice as large for the ryanodine receptor. Both channels also have a similar selectivity for divalent cat ions over monovalent cations, but their selectivities are much lower than the extreme selectivity found with plasma membrane L-type Ca2+ channels, implying different mechanisms of ion permeation between the two intracellular and the plasma membrane Ca2+ channels. Thus, the Ca2+ channel of the IP3 receptor as well as the ryanodine receptor is a rather nonspecific cation selective channel permeable to Ca2+ and monovalent cations, quite a contrast to the actually absolute Ca2+ -selective nature of the L-type Ca2+ channel. The observed similarity of Ca2+ channel properties of the IP3 receptor and the ryanodine receptor is not surprising because these two channels exhibit a remarkable homology in the transmembrane-spanning regions as noted above (44). However, under a physiological condition in the presence of symmetrical 110 mM K+ and luminal free Ca2+ concentration of 2.5 mM, unitary Ca2+ current through the IP3 receptor was estimated to be about 0.5 pA (85), an estimate fourfold lower than that through the ryanodine receptor under the identical conditions. Furthermore, the mean open time of the IP3 receptor under physiological conditions is 3.7 msec (85), while that of the ryanodine receptor is about 20 msec, 5 times longer than that of the IP3 receptor. Thus, the two intracellular Ca2+ channels differ in the amount of Ca2+ released upon opening: the ryanodine receptor discharges about 20 times more Ca2+ per each opening than the IP3 receptor through which 5,400 Ca2+ ions are estimated to be released at every channel opening (85)."

Structure and Function of Inositol 1, 4, 5-Trisphosphate Receptor, Yutaka Yoshida, Shoichi Imai, Department of Pharmacology, Niigata University School of Medicine, The Japanese Journal of Pharmacology, Volume 74 (1997) Issue 2

Source: https://www.jstage.jst.go.jp/article/jphs1951/74/2/74_2_125/_pdf/-char/en (direct full PDF)
Structure and Function of Inositol 1, 4, 5-Trisphosphate Receptor
 
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Human inositol 1,4,5-trisphosphate type-1 receptor, InsP3R1: structure, function, regulation of expression and chromosomal localization.

Abstract

We have isolated cDNA clones encoding an inositol 1,4,5-trisphosphate receptor type 1 (InsP3R1) from human uteri and a leukaemic cell line, HL-60. Northern-blot analysis showed that approx. 10 kb of InsP3R1 mRNA is expressed in human uteri, oviducts and HL-60 cells. The predicted amino acid sequence of human InsP3R1 (2695 amino acids) has 99% identity with that of the mouse SI-/SII- splicing counterpart. Western-blot analysis with anti-(mouse InsP3R1) antibodies showed that InsP3R1 protein of human uteri and oviducts of approx 220 kDa is immunostained. Northern-blot analysis of HL-60 cell differentiation along the neutrophilic lineage induced by retinoic acid or dimethylsulphoxide showed an accompanying enhanced expression of InsP3R1 mRNA. Immunohistochemical analysis of the cerebella of spinocerebellar degeneration patients showed a variable loss of Purkinje cells with an altered pattern of immunostaining. The InsP3R1 gene (Insp3r1) was localized to the 3P25-26 region of human chromosome 3. The data presented here clearly show that InsP3R1 exists widely in human tissues and may play critical roles in various kinds of cellular functions.

Biochem J. 1994 Sep 15; 302(Pt 3): 781–790.
N Yamada, Y Makino, R A Clark, D W Pearson, M G Mattei, J L Guénet, E Ohama, I Fujino, A Miyawaki, T Furuichi
, et al. Department of Molecular Neurobiology, University of Tokyo, Japan.

Source: Human inositol 1,4,5-trisphosphate type-1 receptor, InsP3R1: structure, function, regulation of expression and chromosomal localization. (With full study available)
 
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Receptors Channels. 1993;1(1):11-24.
Widespread expression of inositol 1,4,5-trisphosphate receptor type 1 gene (Insp3r1) in the mouse central nervous system.
Furuichi T1, Simon-Chazottes D, Fujino I, Yamada N, Hasegawa M, Miyawaki A, Yoshikawa S, Guénet JL, Mikoshiba K.
Author information
1
Division of Behavior and Neurobiology, National Institute for Basic Biology, Okazaki, Japan.
Abstract
The expression of inositol 1,4,5-trisphosphate receptor type 1 (InsP3R1) in the mouse central nervous system (CNS) was studied by in situ hybridization. The receptor mRNAs were widely localized throughout the CNS, predominantly in the olfactory tubercle, cerebral cortex, CA1 pyramidal cell layer of the hippocampus, caudate putamen, and cerebellar Purkinje cells, where phosphoinositide turnover is known to be stimulated by various neurotransmitter receptors. In the most abundantly expressing Purkinje cells, InsP3R1 mRNA appeared to be translocated to the distal dendrites, since a strong hybridization density was observed in the molecular layer of the cerebellum. InsP3R protein is known to form tetrameric receptor-channel complex. Our preliminary hybridization data using probes for three distinct InsP3R subtypes showed preferential expression of InsP3R1 in many parts of the CNS. The expression of other receptor subtypes (InsP3R2 and InsP3R3) is less efficient, suggesting that a homotetramer formed of InsP3R1 subtype may play a central part in InsP3/Ca2+ signalling in the neuronal function, whereas a homotetramer of other subtypes and a possible heterotetramer among subtypes may be involved in differential InsP3/Ca2+ signalling. The chromosomal localization of the gene coding for InsP3R1 was confirmed on chromosome 6 but was found to be genetically independent of the Lurcher (Lc) mutation.

Source: Widespread expression of inositol 1,4,5-trisphosphate receptor type 1 gene (Insp3r1) in the mouse central nervous system. - PubMed - NCBI
 
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Cell Calcium. Author manuscript; available in PMC 2013 Feb 14.

Published in final edited form as:
Cell Calcium. 2010 Dec; 48(6): 315–323.
Published online 2010 Nov 13. doi: 10.1016/j.ceca.2010.09.005
PMCID: PMC3572849
NIHMSID: NIHMS433957
PMID: 21075448
The type III inositol 1,4,5-trisphosphate receptor is associated with aggressiveness of colorectal carcinoma
Kazunori Shibao,a Michael J. Fiedler,b Jun Nagata,a Noritaka Minagawa,a Keiji Hirata,c Yoshifumi Nakayama,aYasuko Iwakiri,b Michael H. Nathanson,b and Koji Yamaguchia,*
aDepartment of Surgery I, University of Occupational and Environmental Health School of Medicine, Kitakyushu, Japan
bDigestive Diseases Section, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
cDepartment of Nursing, International University of Health and Welfare, Fukuoka, Japan
*Corresponding author at: Department of Surgery I, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. Tel.: +81 93 691 7255; fax: +81 93 632 1820. pj.ca.u-heou.dem@hcugamay (K. Yamaguchi)
Author information ▼ Copyright and License information ► Disclaimer

The publisher's final edited version of this article is available at Cell Calcium
See other articles in PMC that cite the published article.

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Abstract
The inositol 1,4,5-trisphosphate receptor (InsP3R) mediates Ca2+ signaling in epithelia and regulates cellular functions such as secretion, apoptosis and cell proliferation. Loss of one or more InsP3R isoform has been implicated in disease processes such as cholestasis. Here we examined whether gain of expression of InsP3R isoforms also may be associated with development of disease. Expression of all three InsP3R isoforms was evaluated in tissue from colorectal carcinomas surgically resected from 116 patients. Type I and II InsP3Rs were seen in both normal colorectal mucosa and colorectal cancer, while type III InsP3R was observed only in colorectal cancer. Type III InsP3R expression in the advancing margins of tumors correlated with depth of invasion, lymph node metastasis, liver metastasis, and TNM stage. Heavier expression of type III InsP3R also was associated with decreased 5-year survival. shRNA knockdown of type III InsP3R in CACO-2 colon cancer cells enhanced apoptosis, while over-expression of the receptor decreased apoptosis. Thus, type III InsP3R becomes expressed in colon cancer, and its expression level is directly related to aggressiveness of the tumor, which may reflect inhibition of apoptosis by the receptor. These findings suggest a previously unrecognized role for Ca2+ signaling via this InsP3R isoform in colon cancer.

Source: The type III inositol 1,4,5-trisphosphate receptor is associated with aggressiveness of colorectal carcinoma
 

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