Simulations of Inositol Phosphate Metabolism and Its Interaction with InsP3-Mediated Calcium Release

Mishra, Jyoti; Bhalla, Upinder S.

doi:10.1016/s0006-3495(02)73901-5

Cited by 52 publications

(68 citation statements)

References 68 publications

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“…5c-d). Notwithstanding, the Michaelis-Menten constant of IP 3 -3K for its substrate is experimentally reported to be K 3 ≈ 1 μM [56,59] and it is likely that intracellular IP 3 levels can reach such micromolar concentrations in vivo [73]. Therefore, in the following, we will keep the Michaelis-Menten formulation for v 3K (12).…”

Section: Ip 3 Degradationmentioning

confidence: 99%

Glutamate regulation of calcium and IP3 oscillating and pulsating dynamics in astrocytes

et al. 2009

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Recent years have witnessed an increasing interest in neuron-glia communication. This interest stems from the realization that glia participate in cognitive functions and information processing and are involved in many brain disorders and neurodegenerative diseases. An important process in neuron-glia communications is astrocyte encoding of synaptic information transfer-the modulation of intracellular calcium (Ca 2+ ) dynamics in astrocytes in response to synaptic activity. Here, we derive and investigate a concise mathematical model for glutamate-induced astrocytic intracellular Ca 2+ dynamics that captures the essential biochemical features of the regulatory pathway of inositol 1,4,5-trisphosphate (IP 3 ). Starting from the well-known two-variable (intracellular Ca 2+ and inactive IP 3 receptors) Li-Rinzel model for calcium-induced calcium release, we incorporate the regulation of IP 3 production and phosphorylation. Doing so, we extend it to a three-variable model (which we refer to as the ChI model) that could account for Ca 2+ oscillations with endogenous IP 3 metabolism. This ChI model is then further extended into the G-ChI model to include regulation of IP 3 production by external glutamate signals. Compared with previous similar models, our three-variable models include a more realistic description of IP 3 production and degradation pathways, lumping together their essential nonlinearities within a concise formulation. Using bifurcation analysis and time simulations, we demonstrate the existence of new putative dynamical features. The crosscouplings between IP 3 and Ca 2+ pathways endow the system with self-consistent oscillatory properties and favor mixed frequency-amplitude encoding modes over pure amplitudemodulation ones. These and additional results of our model are in general agreement with available experimental data and may have important implications for the role of astrocytes in the synaptic transfer of information.

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Section: Ip 3 Degradationmentioning

confidence: 99%

Glutamate regulation of calcium and IP3 oscillating and pulsating dynamics in astrocytes

et al. 2009

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“…3). Furthermore, one might argue that the inherent inadequacies of "IP 7 " as a nomenclature have led it occasionally-and incorrectly-to be defined as either a "heptaphosphate" (Mishra and Bhalla, 2002) (i.e., an entirely mythical beast endowed with a chain of seven phosphates) or a "heptakisphosphate" (Lee et al, 2007) (which would require seven phosphates to each be individually attached to a carbon-impossible, of course, because inositol has only six carbons). The usage of "IP 7 /IP 8 " should also be avoided because it can obscure the fact that InsP 6 is not the only precursor for this class of compounds; PP-InsP 4 is a member of this family, but it is synthesized from InsP 5 (Fig.…”

Section: Nomenclaturementioning

confidence: 99%

Diphosphoinositol Polyphosphates: Metabolic Messengers?

Shears¹

2009

Mol Pharmacol

137

148

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The diphosphoinositol polyphosphates ("inositol pyrophosphates") are a specialized subgroup of the inositol phosphate signaling family. This review proposes that many of the current data concerning the metabolic turnover and biological effects of the diphosphoinositol polyphosphates are linked by a common theme: these polyphosphates act as metabolic messengers. This review will also discuss the latest proposals concerning possible molecular mechanisms of action of this intriguing class of molecules.The discovery of cyclic AMP Sutherland and Rall, 1958) introduced us to the concept of a "second messenger" (Robison et al., 1968): a diffusible molecule (or ion) that, in response to an extracellular stimulus, is rapidly generated at (or released from) a particular subcellular site and then regulates particular effector proteins within the cell so as to elicit a cellular response. Of course, evolution has a remarkable tendency to repeat a good idea, so many different second messengers are now known. The inositol phosphate family represents the convergence of several "good signaling ideas," most notably in their use of a recurring theme in the cell-signaling genre: phosphate groups. Phosphates have two especially prominent features that facilitate specificity of interactions between cell signaling entities. First, the bulky nature of the phosphate group imposes geometric constraints on ligand-protein and protein-protein interactions. Second, the phosphate's negative charge at physiological pH bestows specificity on its interactions with target proteins through multiple ionic and hydrogen bonds. The negative charges on the phosphate group also make soluble, phosphorylated molecules lipid-impermeant, so that they can be retained inside cells.Inositol offers several additional assets for a signaling molecule. It is chemically stable, it is small (hence it diffuses through cytosol quickly), and it is only a short synthetic offshoot from the glycolytic pathway (Sherman et al., 1977). There is also a functionally significant plane of symmetry across the 2/5-axis of the inositol ring (Fig. 1). That symmetry permits one inositol phosphate to imitate another's threedimensional phosphate recognition pattern when the orientation of the inositol ring changes in relation to the protein's ligand-binding site (Wilcox et al., 1994), although in addition the binding site itself has to be somewhat flexible . This phenomenon provides a molecular explanation for the metabolic promiscuity of certain inositol phosphate kinases (for review, see Shears, 2004), and it also facilitates functionally important metabolic interactions between differ-

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“…This model consists of about 100 non-linear ordinary differential equations (ODEs) and algebraic equations and about 200 parameters. Similarly, a detailed model for calcium signalling consists of about 200 equations and even higher number of parameters [9]. The complexity becomes even more appreciable when a network model corresponding to the whole cell, possibly resulting in tens of thousands of non-linear mixed (both continuous and discrete variables) equations with a similar number of parameters, needs to be studied.…”

Section: Introductionmentioning

confidence: 99%

Reduced-order modelling of biochemical networks: application to the GTPase-cycle signalling module

Maurya

Bornheimer

Venkatasubramanian

et al. 2005

IEE Proc. Syst. Biol.

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Biochemical systems embed complex networks and hence development and analysis of their detailed models pose a challenge for computation. Coarse-grained biochemical models, called reduced-order models (ROMs), consisting of essential biochemical mechanisms are more useful for computational analysis and for studying important features of a biochemical network. The authors present a novel method to model-reduction by identifying potentially important parameters using multidimensional sensitivity analysis. A ROM is generated for the GTPase-cycle module of m1 muscarinic acetylcholine receptor, Gq, and regulator of G-protein signalling 4 (a GTPaseactivating protein or GAP) starting from a detailed model of 48 reactions. The resulting ROM has only 17 reactions. The ROM suggested that complexes of G-protein coupled receptor (GPCR) and GAP -which were proposed in the detailed model as a hypothesis -are required to fit the experimental data. Models previously published in the literature are also simulated and compared with the ROM. Through this comparison, a minimal ROM, that also requires complexes of GPCR and GAP, with just 15 parameters is generated. The proposed reduced-order modelling methodology is scalable to larger networks and provides a general framework for the reduction of models of biochemical systems.

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Simulations of Inositol Phosphate Metabolism and Its Interaction with InsP3-Mediated Calcium Release

Cited by 52 publications

References 68 publications

Glutamate regulation of calcium and IP3 oscillating and pulsating dynamics in astrocytes

Glutamate regulation of calcium and IP3 oscillating and pulsating dynamics in astrocytes

Diphosphoinositol Polyphosphates: Metabolic Messengers?

Reduced-order modelling of biochemical networks: application to the GTPase-cycle signalling module

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