Inositol Trisphosphate Receptor Ca2+ Release Channels

Department of Physiology, University of Pennsylvania, Philadelphia 19104-6085, USA.
Physiological Reviews (Impact Factor: 27.32). 05/2007; 87(2):593-658. DOI: 10.1152/physrev.00035.2006
Source: PubMed


The inositol 1,4,5-trisphosphate (InsP3) receptors (InsP3Rs) are a family of Ca2+ release channels localized predominately in the endoplasmic reticulum of all cell types. They function to release Ca2+ into the cytoplasm in response to InsP3 produced by diverse stimuli, generating complex local and global Ca2+ signals that regulate numerous cell physiological processes ranging from gene transcription to secretion to learning and memory. The InsP3R is a calcium-selective cation channel whose gating is regulated not only by InsP3, but by other ligands as well, in particular cytoplasmic Ca2+. Over the last decade, detailed quantitative studies of InsP3R channel function and its regulation by ligands and interacting proteins have provided new insights into a remarkable richness of channel regulation and of the structural aspects that underlie signal transduction and permeation. Here, we focus on these developments and review and synthesize the literature regarding the structure and single-channel properties of the InsP3R.

Download full-text


Available from: Carl White
    • "ctly or indirectly ( Fiacco and McCarthy , 2006 ) . There is also a wealth of research demonstrating crosstalk between the cal - cium signaling apparatus and other second messenger signal - ing networks ( Bruce et al . , 2003 ; Clementi and Meldolesi , 1997 ) , perhaps best exemplified by the range of signals that converge on the InsP 3 receptor ( Foskett et al . , 2007 ) . This suggests that coincident activation of neurotransmitter recep - tors coupled to calcium release and modulatory receptors coupled to pathways that affect calcium signaling could alter the probability of generating a global calcium response . Endocannabinoid signaling mediates neuromodulation in many neuronal classes and many bra"
    [Show abstract] [Hide abstract]
    ABSTRACT: Astrocyte calcium signals can range in size from subcellular microdomains to waves that spread through the whole cell (and into connected cells). The differential roles of such local or global calcium signaling are under intense investigation, but the mechanisms by which local signals evolve into global signals in astrocytes are not well understood, nor are the computational rules by which physiological stimuli are transduced into a global signal. To investigate these questions, we transiently applied receptor agonists linked to calcium signaling to primary cultures of cerebellar astrocytes. Astrocytes repetitively tested with the same stimulus responded with global signals intermittently, indicating that each stimulus had a defined probability for triggering a response. The response probability varied between agonists, increased with agonist concentration, and could be positively and negatively modulated by crosstalk with other signaling pathways. To better understand the processes determining the evolution of a global signal, we recorded subcellular calcium "puffs" throughout the whole cell during stimulation. The key requirement for puffs to trigger a global calcium wave following receptor activation appeared to be the synchronous release of calcium from three or more sites, rather than an increasing calcium load accumulating in the cytosol due to increased puff size, amplitude, or frequency. These results suggest that the concentration of transient stimuli will be encoded into a probability of generating a global calcium response, determined by the likelihood of synchronous release from multiple subcellular sites. GLIA 2015.
    No preview · Article · Dec 2015 · Glia
  • Source
    • "The basic structure of IP3Rs has two major sites of homology between the subtypes: the N-terminal region with the binding site for IP3 (Mignery and Sudhof 1990; Sudhof et al. 1991; Yoshikawa et al. 1996) and the C-terminus with the channel domain and the tetramer formation determinants (Michikawa et al. 1994; Boehning et al. 2001). The central modulatory or coupling domain that contains several interaction sites for many intracellular regulators and interacting proteins is the intervening domain (~1700 a. a.) that exhibits more sequence variability between subtypes (Missiaen et al. 1992a; Patterson and Boehning 2004; Bezprozvanny 2005; Mikoshiba 2007a, 2007b; Foskett et al. 2007). By far, the largest amount of information about regulatory mechanisms is available for IP3R1, while the other subtypes are less extensively documented . "

    Full-text · Dataset · Oct 2015
  • Source
    • "There is less information on the number and localisation of Ca 2+ binding sites. Because localisation of Ca 2+ binding sites by mutation studies has been difficult , Foskett et al. [31] infer various Ca 2+ binding sensors from the observed co-regulation by IP 3 and Ca 2+ , see Foskett and Mak [30] for a summary. Often models assume a certain number of IP 3 and Ca 2+ binding sites and represent binding and unbinding of these ligands as transitions between states regulated by mass action kinetics. "
    [Show description] [Hide description]
    DESCRIPTION: We give a review of the current state of the art of data-driven modelling of the inositol trisphosphate receptor (IPR). After explaining that the IPR plays a crucial role as a central regulator in calcium dynamics, several sources of relevant experimental data are introduced. Single ion channels are best studied by recording single-channel currents under different ligand concentrations via the patch-clamp technique. The particular relevance of modal gating, the spontaneous switching between different levels of channel activity that occur even at constant ligand concentrations, is highlighted. In order to investigate the interactions of IPRs, calcium release from small clusters of channels, so-called calcium puffs, can be used. We then present the mathematical framework common to all models based on single-channel data, aggregated continuous-time Markov models, and give a short review of statistical approaches for parameterising these models with experimental data. The process of building a Markov model that integrates various sources of experimental data is illustrated using two recent examples, the model by Ullah et al. and the "Park-Drive" model by Siekmann et al., the only models that account for all sources of data currently available. Finally, it is demonstrated that the essential features of the Park-Drive model in different models of calcium dynamics are preserved after reducing it to a two-state model that only accounts for the switching between the inactive "park" and the active "drive" mode. This highlights the fact that modal gating is the most important mechanism of ligand regulation in the IPR. It also emphasises that data-driven models of ion channels do not necessarily have to lead to detailed models but can be constructed so that relevant data is selected to represent ion channels at the appropriate level of complexity for a given application.
    Full-text · Research · Jul 2015
Show more