Soni Kamal Kumar. et al. / International Journal of Biological & Pharmaceutical Research. 2014; 5(2):

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1 120 e- ISSN Print ISSN International Journal of Biological & Pharmaceutical Research Journal homepage: IJBPR CONFIRMATION OF INOSITOL-1, 4, 5-TRIPHOSPHATE RECEPTOR AND CA 2+ :A COMPREHENSIVE REVIEW OF COMPLEX RELATIONSHIPS FOR TYPE-2 DIABETES *Soni Kamal Kumar, Arya Rakesh, Tiwari Archana School of Biotechnology, Rajiv Gandhi Proudyogiki Vishwavidyalaya (State Technological University of Madhya Pradesh) Airport Bypass Road, Bhopal , India. ABSTRACT Type-2 diabetes rapidly disseminates across the world. Ca2+ and Inositol-1, 4, 5- triphosphate (IP 3) are universal intracellular messenger vital for the opening of Inositol 1, 4, 5-trisphosphate receptors (IP3R or intracellular Ca2+release channels). Major problem in type-2 diabetes is abating the amount of insulin in the pancreas by depletion of Ca2+ in cytoplasm. IP3 will be activated by the presence of growth hormone resulting in elevation of the Ca2+ level in the cytoplasm followed by paucity of Ca2+ levels in the endoplasmic reticulum. This review emphasizes a comprehensive overview of the current information available on changes occurring in the confirmation of IP3 receptor by IP3 and control of intracellular Ca2+signaling and this will be propitious in order to develop a new drug for the control of diabetes mellitus type-ii. Key Words: Insulin signaling, Pancreatic Function, Insulin Secretion, Ca2+ signaling, Diabetes mellitus type-2. INTRODUCTION Calcium is celestial and omnipresent messenger of the cell, it plays very important role in the intracellular signaling on the cytoplasm, and other cellular organelles like mitochondria, endoplasmic reticulum as well as nucleus, whereas Lots of process or mechanism in the cell can regulate the signaling of the calcium. These processes can induce and inhibit the cellular Ca 2+ signaling. If some disturbance occurs in these processes they will be caused some many types of diseases (Missiaen L et al., 2000) like Type 1- child or juvenile or (IDDM) diabetes mellitus, Type 2- diabetes (NIDDM) or Adult -onset diabetes or insulin resistance diabetes mellitus, Type 3- diabetes mellitus (Brain insulin diabetes), Gestational diabetes mellitus (GDM or Early pregnancy diabetes). Ca 2+ mobilizing agonist was added to the its receptors on Corresponding Author Kamal Kumar Soni kamal_rkdf@yahoo.com plasma membrane results the increase the number of calcium ion in the cytoplasm which persist the absence of extracellular concentration of calcium ion, after that will be secreted from intracellular store. This is the strongest evidence to show IP 3 mediate calcium ion concentration in cytoplasm (Berridge MJ, 1987). The amount of Ca 2+ in the cell will be controlled by some different types of process those are operating at the same time in a concurrent manner, these are classified in Ca 2 + start and Ca 2+ stop mechanism depending on whether they serve to increase or decrease cytosolic Ca 2+. However, the most commonly observed process of regulated Ca 2+ entry in non-excitable cells is a process known as capacitive Ca 2+ entry or storeoperated Ca 2+ entry (Puntey, JW, 1986; Putney JW, 1997). In this process the decreasing of intracellular stores Ca 2+ by the activation of Inositol-1,4,5-triphosphate or other different types of Ca- releasing impulse stimulates a signaling way to opening the Ca 2+ channels of the plasma membrane (Parekh AB and Penner R, 1997; Barritt GJ, 1999; Berridge MJ, 1993).

2 121 In signaling, the regulation of calcium depends on different type of channels and receptors those are exist on the cell surface, They will regulate the Ca 2+ mobilizations between intracellular stores and cytoplasm. Some biochemical messenger like, IP 3 cyclic ADP Ribose (cadpr) and nicotinic acid di- nucleotide phosphate (NAADP) was involved by channel regulatory mechanism. If growth factors or hormones were bound to its specific receptors, caused stimulate the activation of a specific enzyme and these enzymes will produce inositol-1, 4, 5-triphosphate from phospholipids after catalysis reaction. IP 3 is the hydrophilic compound but basically it was derived from a lipid moiety. This water soluble or hydrophilic property of IP 3 provides easily expansion inside the cell or in the cytoplasm. IP 3 will bind to IP 3 receptor present on Endoplasmic reticulum or sarcoplasmic reticulum, the structure of IP 3 R will be changed and the channel is opened, and calcium exit out from the ER and the influx into cytoplasm. In which the concentration of Ca 2+ will be decreased in the ER and an increase in the cytoplasm. While discussing IP 3 receptors (IP 3 R), the function of IP 3 starts through binding to membrane associated IP 3 R (Berridge MJ et al., 2000; Berridge MJ et al., 2003). If IP 3 is bind with IP 3 R they causes increase its sensitivity to calcium ion and increase mobilization of calcium ion (Nadif Kasri N et al., 2002). There are three different types of IP 3 R are present in mammals IP 3 R1, IP 3 R2 and IP 3 R3 (Furuichi T et al., 1994; Patel S et al., 1999). There are two types of arrangement of tetramer were evolved for the formation of a Ca 2+ channel of these IP 3 R, homotetramer and heterotetramer (Patel S et al., 1999). IP 3 R1 was mostly studied type of IP 3 R, and they were found in high number in the central nervous system s cell from cerebellar Purkinje cells (Furuichi T et al., 1993; Worley PF et al., 1987). There are lots of 3D structure of IP 3 obtained recently with a resolution around 30 Aº (Jiang QX et al., 2002; Hamada K et al., 2003; Da Fonseca PC et al., 2003; Serysheva et al., 2003; Sato C et al., 2004) have provided plenty of information on the IP 3 R confirmation. Now very high resolution structure of IP 3 R is present in the complex of IP 3 -binding core with IP 3 (Bosanac I et al., 2002). The aim of this review is that the changing of the confirmation of IP 3 R and opening the calcium channel for the mobilization of calcium ion from the sarcoendoplasmic reticulum to the cytoplasm will be regulated by IP 3. The structure of IP 3 R plays an important role in the performance of most of the cellular signaling. They have a different confirmation for binding of IP 3 and facilitate to form a calcium channel to transfer of calcium from inside of the endoplasmic reticulum to the cytoplasm. This pathway plays major role in the secretion of insulin from the pancreatic beta cell, It could be utilized as a beneficial strategy in research studies aiming to decrease blood sugar levels. Molecular Structure of IP 3 R The molecular structure of mammalian IP 3 R1, there are three operatively specific domainswithin these receptors, 2479 residues having polypeptide (Furuichi T et al., 1989) (Figure1) : the N-terminal part is responsible for binding of IP 3, and C-terminal part is responsible for channel formation, and regulatory site is present between both parts (Mignery GA and Sudhof TC, 1990; Miyawaki A et al., 1991) These three regions are necessary to perform regulation of IP 3 receptors as shown in fig: 2. For the binding of IP 3 the responsible region was residue in the N - terminal region (Yoshikawa F et al., 1996). Pre 226 residues are responsible for the inhibition of binding of IP 3 to receptor, hence known as suppressor domain (Yoshikawa F et al., 1996). For the creation of the channel there are six transmembrane helices are present within 2276 to 2589 residues in the C terminal (Yoshikawa F et al., 1992). Remaining residue known as a coupling domain in the C terminal (Uchida K et al., 2003). Formation of INS (145) P 3 In the formation IP 3, kinase enzyme plays an important role for the phosphorylation of Phosphateidylinositol (PI) in the cell to form phosphatidylinositol-4-phosphate (PIP) and phosphatidylinositol - 4,5 -bisphosphate (PIP 2 ) ( Kirk CJ et al., 1981). Hydrolysis of PIP 2 catalyzed by Phospholipase-C results water-soluble inositol (1, 4, 5) trisphosphate [(1, 4, 5) IP 3 ] and lipid-soluble diacylglycerol was formed (Berridge MJ, 1983). Phosphoinositide phospholipase C (PLC) is the responsible enzyme in the formation of InsP 3, which become stimulated when growth factor bind to respective receptor on the plasma membrane. InsP 3 can produced from phospholipidphosphatidyl inositol-4,5-diphosphate with excretion of DAG (Nowycky MC and Thomas AP, 2002). IP 3 are basically a very common messenger, they can activate the IP 3 R receptor are associated IP 3 channel, those cause exits of Ca 2+ from inside the store in the endoplasmic reticulum. The calcium (Ca 2+ ) level increase in the cytoplasm, and they cause the changing the potential between inside and outside of the membrane. After that assumed the Effect of (1, 4, 5) IP 3 on Ca 2+ transfer was demonstrated; rapidly released Ca 2+ from a store in mitochondrial by increasing the micro molar concentrations ofip 3 in pancreatic acinar cells (Streb H et al., 1983).The large number of laboratories has confirmed this result in many types of tissue (Burgess, G.M et al., 1984; Joseph SK et al., 1984). Pathway of Regulation By InsP 3 Below diagram illustrates the various phases or step of InsP 3 (Inositol 1, 4, 5, triphosphate) pathway or cascade (Figure 5) (Thatcher JD, 2010; Violin JD and

3 122 Newton AC, 2003). Many cellular and molecular processes are regulated by this pathway of IP 3. In which the signaling start by acetylcholine and thyroid stimulating hormone, they are binds to heterotrimeric guanine. Nucleotide binding protein (G-protein) -coupled receptors (GPCRs) or tyrosine kinase receptors (rtks). After binding the receptor become activated them leads to activation of phospholipase C (PLC), which formed IP 3 and diacylglycerol (DAG) from phosphatidylinositol 4, 5- bisphosphate (PIP 2 ). IP 3 can bind to IP 3 R in endoplasmic plastic membrane and change the confirmation of IP 3 R (Figure 6) (Bosanac I et al., 2004) In the above figure(a) There are two domains of IP 3 Rcore are shown in this figure (the β-domain b and the α-domain a ) joint through hinge region. If IP 3 is absence both domains are moving in a free manner with respect to each other. (B) IP 3 can bind both of domains Fig 1. Attachment of growth factors or hormone to the receptor and activation of PLC. and decrease free movements of them.(c) IP 3 Rsup c can bind both of domains like IP 3 and formation of the hinge II region. If IP 3 are absent IP 3 Rsup can direct interact with both of domains (IP 3 Rcore) and cause disruption of the interaction between IP 3 and Ca 2+ binding site are not performed in a proper manner and does not bind its proper legands. If IP 3 can bind they can removal of IP 3 Rsup from IP 3 core, and allow to bind Ca 2+ with this core domain (Bosanac I et al., 2004). After changing the confirmation of IP 3 R, release of Ca 2+ from the endoplasmic reticulum and regulates the sensitivity of various types of downstream processes and targets. Targets mean the activation of different types of enzymes like PKC. DAG can activate to PKC with the help of Ca 2+.Cytosolic Ca 2+ has an important role in the secretion of insulin from insulin vesicles. Ca 2+ can cause the stimulation of insulin secretion mostly by IP 3 R. Fig 2. Molecular structural domains of IP 3 receptors in which five main regions are suppressor domain residue, IP 3 -binding core residue, modular and transducing domain residue, channel domain and coupling domain residue, those are responsible for regulation of IP 3 R (Patterson RL, Snyder SH, 2004). Fig 3. Formations of PIP and PIP 2 from Phosphatidylinositol (PI) with help of Kinase enzyme. Fig 4. formations of Inositol-1, 4,5-triphosphate. This figure represents a summary of the formation of the InsP 3 by Phosphatidyl inositide phospholipase C (PLC) with the removal of diacylglycerol (DAG)

4 123 Fig 5. Inositol-1, 4, 5-triphosphate (InsP 3 ) signaling pathway. Fig 6. Conformational changes in of IP3Rcore (receptor domains) α.and β in the presence of IP 3 DISCUSSION AND CONCLUSION In this study several overlooked concepts have been discussed about its function and structure. IP 3 is an important element to regulate the changes of the confirmation in the IP 3 R in which there are three regions are responsible for regulation of Ca 2+ signaling, C- terminal, N-terminal and regulatory region. In the N- terminal region suppressor domain and IP 3 binding core are responsible for activation and inhibition of IP 3 R. Currently our entire understanding of the mechanisms by which changes in confirmation occur in IP 3 R with the help of inositol-1, 4, 5-triphosphates, are also capable to control the regulation of Ca 2+ -signaling.whereas IP 3 has been accepted as the Signal transfer messenger for intracellular Ca 2+ release from the IP 3 R associated calcium channel. Moreover, the Phosphatidylinositol dissociates into inositol-1, 4, 5-triphosphates and Phosphatidyl inositol-1, 4-bis phosphate. IP 3 acts as a positive element to IP 3 R and calcium acts as regulator for IP 3 R based on the concentration of Ca 2+ inside the endoplasmic reticulum and the cytoplasm. Hence with the help of current study it could be proposed that the phosphoinositol-1, 4, 5- triphosphate plays an important role in the Ca 2+ Signaling, and helps toincrease insulin secretion. These strategies are used for the development of new controlling therapy of diabetes mellitus type-ii. ACKNOWLEDGEMENTS I wish to acknowledge my parents Mr. R G Soni and Mrs. Girija Soni their patience, love and undying support. I would have been unable to accomplish the following review paper if not for their blessings and the fact that I have been exempted from all my responsibilities towards them to pursue my passion for research. With a deep sense of gratitude, I wish to express my sincere thanks to my supervisor, Dr. Archana Tiwari, HOD, School of Biotechnology, RGPV and my project supervisor has been like my parent. She has provided generous support throughout my stay at RGPV. REFERENCES Barritt GJ. Receptor-activated Ca2+ inflow in animal cells: a variety of pathways tailored to meet different intracellular Ca2+ signalling requirements. Biochem J. 1999; 337(Pt 2): Berridge MJ, Bootman MD and Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 2003; 4(7): Berridge MJ, Lipp P and Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol. 2000; 1(1): Berridge MJ. Inositol trisphosphate and calcium signalling. Nature. 1993; 361(6410): Berridge MJ. Inositol trisphosphate and diacylglycerol: two interacting second messengers. Annu Rev Biochem. 1987; 56: Berridge MJ. Rapid accumulation of inositol trisphosphate reveals that agonists hydrolyse polyphosphoinositides instead of phosphatidylinositol. Biochem J. 1983; 212(3): Bosanac I et al., Structural insights into the regulatory mechanism of IP3 receptor. Biochim Biophys Acta. 2004; 1742(1-3): Bosanac I et al., Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand. Nature. 2002; 420(6916):

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