The inositol 1,4,5-trisphosphate receptors

doi:10.1016/j.ceca.2005.06.030

Cell Calcium

Volume 38, Issues 3–4, September–October 2005, Pages 261-272

https://doi.org/10.1016/j.ceca.2005.06.030 Get rights and content

Abstract

The inositol (1,4,5)-trisphosphate receptors (InsP₃R) are the intracellular calcium (Ca²⁺) release channels that play a key role in Ca²⁺ signaling in cells. Three InsP₃R isoforms—InsP₃R type 1 (InsP₃R1), InsP₃R type 2 (InsP₃R2), and InsP₃R type 3 (InsP₃R3) are expressed in mammals. A single InsP₃R isoform is expressed in Drosophila melanogaster (DmInsP₃R) and Caenorhabditis elegans (CeInsP₃R). The progress made during last decade towards understanding the function and the properties of the InsP₃R is briefly reviewed in this chapter. The main emphasis is on studies that revealed structural determinants responsible for the ligand recognition by the InsP₃R, ion permeability of the InsP₃R, modulation of the InsP₃R by cytosolic Ca²⁺, ATP and PKA phosphorylation and on the recently identified InsP₃R-binding partners. The main focus is on the InsP₃R1, but the recent information about properties of other InsP₃R isoforms is also discussed.

Introduction

Ten years ago together with Barbara Ehrlich we published a topical review in the Journal of Membrane Biology [1] in which we summarized major functional properties of the inositol 1,4,5-trisphosphate receptors (InsP₃R). In approximately the same time, Teiichi Furuichi, Katsuhiko Mikoshiba and colleagues published a review in Current Opinion in Neurobiology [2], in which they summarized known information about molecular structure of the InsP₃R. The main effort during last decade has been focused on trying to merge the “functional” [1] and “molecular” [2] views of the InsP₃R into one coherent image. Here, I will briefly review the progress made so far. From the beginning I would like to apologize to many colleagues whose papers I was not able to discuss here due to space limitations of this review format. A number of laboratories around the world used a variety of experimental systems to perform structure-functional analysis of the InsP₃R. The most fruitful approaches turned out to be (1) to analyze Ca²⁺ signals supported by wild-type and mutant InsP₃R expressed in DT40 cell line with all three InsP₃R genes genetically knocked out [3]; (2) to analyze single channel behavior of wild-type and mutant InsP₃R expressed in mammalian cell lines followed by purification and reconstitution into planar lipid bilayers; (3) to analyze single channel behavior of wild-type and mutant InsP₃R expressed in Sf9 cells by baculoviral infection followed by reconstitution into planar lipid bilayers; (4) to analyze single channel behavior of wild-type and mutant InsP₃R expressed in Xenopus oocytes by cRNA injection followed by nuclear patch recordings. Due to different approaches used by multiple groups some of the obtained results are controversial, but in this review I will attempt to focus on consensus that has recently began to emerge. The main structure-function effort has been focused on type 1 mammalian InsP₃R (InsP₃R1) and I will primarily discuss InsP₃R1 results. More recently some information about properties of mammalian InsP₃R2, mammalian InsP₃R3, Drosophila melanogaster InsP₃R, and Caenorhabditis elegans InsP₃R started to emerge and these data will also be discussed briefly.

Section snippets

InsP₃R1

What have we learned about InsP₃R1 during the last decade? Here is what we knew in 1995: (1) InsP₃R1 channel is a tetramer of four subunits 2749 amino acids (for rat) each; (2) each InsP₃R1 subunit composed of amino-terminal InsP₃-binding domain, carboxy-terminal channel-forming domain, and the middle coupling (modulatory) domain; (3) InsP₃R1 are high conductance moderately divalent cation-selective channels gated by InsP₃; (4) InsP₃R1 display bell-shaped dependence on cytosolic Ca²⁺ in

InsP₃R2 and InsP₃R3

When compared to the InsP₃R1, we know a lot less about properties of other two mammalian InsP₃R isoforms—InsP₃R2 and InsP₃R3. The InsP₃R2 is a 2701 amino acid (in rat) protein that is 70.5% identical to the InsP₃R1. The InsP₃R3 is a 2670 amino acid (in rat) protein that is 64.6% identical to the InsP₃R1. The local similarity analysis reveals that mammalian InsP₃R are composed of highly conserved regions (>70% identity) separated by highly variable regions (<50% identity) (Fig. 4). Remarkably,

DmInsP₃R and CeInsP₃R

A single copy of the InsP₃R gene (itpr) is present in the genome of D. melanogaster [94], [95], a model organism, that has been used widely for genetic screens. The null alleles of itrp are lethal at second instar larvae stage [96]. The Drosophila InsP₃R (DmInsP₃R) is 2828 amino acid protein that shares 60.8% sequence identity with the mammalian InsP₃R1 (Fig. 4). Embryonic and adult head (AH) splice variants of DmInsP₃R have been isolated [97]. The AH-DmInsP₃R splice variant contains a nine

Future directions

As I attempted to outline in this review, during last decade we collectively made a tremendous progress towards understanding the structural determinants and mechanisms of the InsP₃R1 function. We also started to gather information about other InsP₃R isoforms. What can we expect to learn in the next 10 years? In my opinion, the field will follow along these five major directions:

(1)
The complete structure of the InsP₃R will be determined at atomic resolution. Several groups already determined low

Acknowledgments

I am grateful to many talented students in my lab for their hard work and dedication, to Gregory Mignery and Thomas C. Südhof for the kind gift of the rat InsP₃R1 and InsP₃R2 clones, to Dr. Graem Bell for the kind gift of the rat InsP₃R3 clone, to Masamitsu Iino, Humbert De Smedt, and Gaiti Hasan for great collaborations and to Barbara Ehrlich for lots of encouragement and support. The InsP₃R project in my laboratory is supported by the Welch Foundation and NIH R01 NS38082.

References (117)

T. Furuichi et al.
Intracellular channels
Curr. Opin. Neurobiol.
(1994)
F. Yoshikawa et al.
Trypsinized cerebellar inositol 1,4,5-trisphosphate receptor. Structural and functional coupling of cleaved ligand binding and channel domains
J. Biol. Chem.
(1999)
I. Bosanac et al.
Crystal structure of the ligand binding suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor
Mol. Cell
(2005)
J.C. Tu et al.
Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors
Neuron
(1998)
J.P. Yuan et al.
Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors
Cell
(2003)
L.P. Haynes et al.
Calcium-binding protein 1 is an inhibitor of agonist-evoked, inositol 1,4,5-trisphosphate-mediated calcium signaling
J. Biol. Chem.
(2004)
F. Yoshikawa et al.
Mutational analysis of the ligand binding site of the inositol 1,4,5-trisphosphate receptor
J. Biol. Chem.
(1996)
F. Yoshikawa et al.
Cooperative formation of the ligand-binding site of the inositol 1,4,5-trisphosphate receptor by two separable domains
J. Biol. Chem.
(1999)
J. Ramos-Franco et al.
Single channel function of recombinant type-1 inositol 1,4,5-trisphosphate receptor ligand binding domain splice variants
Biophys. J.
(1998)
F.C. Nucifora et al.
Molecular cloning of a cDNA for the human inositol 1,4,5-trisphosphate receptor type 1, and the identification of a third alternatively spliced variant
Brain Res. Mol. Brain Res.
(1995)

H. Ando et al.

IRBIT, a novel inositol 1,4,5-trisphosphate (IP3) receptor-binding protein, is released from the IP3 receptor upon IP3 binding to the receptor

J. Biol. Chem.

(2003)

H. Tu et al.

Association of type 1 inositol 1,4,5-trisphosphate receptor with AKAP9 (Yotiao) and protein kinase A

J. Biol. Chem.

(2004)

T.S. Tang et al.

Dopamine receptor-mediated Ca(2+) signaling in striatal medium spiny neurons

J. Biol. Chem.

(2004)

T. Michikawa et al.

Calmodulin mediates calcium-dependent inactivation of the cerebellar type 1 inositol 1,4,5-trisphosphate receptor

Neuron

(1999)

A.M. Cameron et al.

Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2+ flux

Cell

(1995)

A.M. Cameron et al.

FKBP12 binds the inositol 1,4,5-trisphosphate receptor at leucine- proline (1400–1401) and anchors calcineurin to this FK506-like domain

J. Biol. Chem.

(1997)

M. Carmody et al.

FKBP12 associates tightly with the skeletal muscle type 1 ryanodine receptor, but not with other intracellular calcium release channels

FEBS Lett.

(2001)

C.D. Ferris et al.

Inositol 1,4,5-trisphosphate receptor is phosphorylated by cyclic AMP-dependent protein kinase at serines 1755 and 1589

Biochem. Biophys. Res. Commun.

(1991)

L.S. Haug et al.

Phosphorylation of the inositol 1,4,5-trisphosphate receptor by cyclic nucleotide-dependent kinases in vitro and in rat cerebellar slices in situ

J. Biol. Chem.

(1999)

P. Komalavilas et al.

Phosphorylation of the inositol 1,4,5-trisphosphate receptor by cyclic GMP-dependent protein kinase

J. Biol. Chem.

(1994)

K. Maes et al.

Adenine-nucleotide binding sites on the inositol 1,4,5-trisphosphate receptor bind caffeine, but not adenophostin A or cyclic ADP-ribose

Cell Calcium

(1999)

K. Maes et al.

Mapping of the ATP-binding sites on inositol 1,4,5-trisphosphate receptor type 1 and type 3 homotetramers by controlled proteolysis and photoaffinity labeling

J. Biol. Chem.

(2001)

J. Hirota et al.

Inositol 1,4,5-trisphosphate receptor type 1 is a substrate for caspase-3 and is cleaved during apoptosis in a caspase-3-dependent manner

J. Biol. Chem.

(1999)

H. Tu et al.

Functional characterization of the type 1 inositol 1,4,5-trisphosphate receptor coupling domain SII(±) splice variants and the opisthotonos mutant form

Biophys. J.

(2002)

S. Nakade et al.

Cyclic AMP-dependent phosphorylation of an immunoaffinity-purified homotetrameric inositol 1,4,5-trisphosphate receptor (type I) increases Ca2+ flux in reconstituted vesicles

J. Biol. Chem.

(1994)

R.J. Wojcikiewicz et al.

Phosphorylation of inositol 1,4,5-trisphosphate receptors by cAMP-dependent protein kinase. Type I, II, and III receptors are differentially susceptible to phosphorylation and are phosphorylated in intact cells

J. Biol. Chem.

(1998)

L.E. Wagner et al.

Phosphorylation of type-1 inositol 1,4,5-trisphosphate receptors by cyclic nucleotide-dependent protein kinases: a mutational analysis of the functionally important sites in the S2+ and S2− splice variants

J. Biol. Chem.

(2003)

L.E. Wagner et al.

Functional consequences of phosphomimetic mutations at key cAMP-dependent protein kinase phosphorylation sites in the type 1 inositol 1,4,5-trisphosphate receptor

J. Biol. Chem.

(2004)

A. Ammendola et al.

Molecular determinants of the interaction between the inositol 1,4,5-trisphosphate receptor-associated cGMP kinase substrate (IRAG) and cGMP kinase Ibeta

J. Biol. Chem.

(2001)

Z. Assefa et al.

Caspase-3-induced truncation of type 1 inositol trisphosphate receptor accelerates apoptotic cell death and induces inositol trisphosphate-independent calcium release during apoptosis

J. Biol. Chem.

(2004)

H. Tu et al.

Functional and biochemical analysis of the type 1 inositol (1,4,5)-trisphosphate receptor calcium sensor

Biophys. J.

(2003)

H. Tu et al.

Modulation of mammalian inositol 1,4,5-trisphosphate receptor isoforms by calcium: a role of calcium sensor region

Biophys. J.

(2005)

S.R. Chen et al.

Molecular identification of the ryanodine receptor Ca2+ sensor

J. Biol. Chem.

(1998)

T. Michikawa et al.

Transmembrane topology and sites of N-glycosylation of inositol 1,4,5-trisphosphate receptor

J. Biol. Chem.

(1994)

S.K. Joseph et al.

Membrane insertion, glycosylation, and oligomerization of inositol trisphosphate receptors in a cell-free translation system

J. Biol. Chem.

(1997)

D. Boehning et al.

Molecular determinants of ion permeation and selectivity in inositol 1,4,5-trisphosphate receptor Ca2+ channels

J. Biol. Chem.

(2001)

S. Srikanth et al.

Functional properties of a pore mutant in the Drosophila melanogaster inositol 1,4,5-trisphosphate receptor

FEBS Lett.

(2004)

D.L. Galvan et al.

Subunit oligomerization, and topology of the inositol 1,4,5-trisphosphate receptor

J. Biol. Chem.

(1999)

L.Y. Bourguignon et al.

Identification of the ankyrin-binding domain of the mouse T-lymphoma cell inositol 1,4,5-trisphosphate (IP3) receptor and its role in the regulation of IP3-mediated internal Ca2+ release

J. Biol. Chem.

(1995)

P.J. Mohler et al.

Inositol 1,4,5-trisphosphate receptor localization and stability in neonatal cardiomyocytes requires interaction with ankyrin-B

J. Biol. Chem.

(2004)

S.H. Yoo et al.

Interaction of chromogranin B and the near N-terminal region of chromogranin B with an intraluminal loop peptide of the inositol 1,4,5-trisphosphate receptor

J. Biol. Chem.

(2000)

S.H. Yoo et al.

pH-dependent interaction of an intraluminal loop of inositol 1,4,5-trisphosphate receptor with chromogranin A

FEBS Lett.

(1994)

E.C. Thrower et al.

Activation of the inositol 1,4,5-trisphosphate receptor by the calcium storage protein chromogranin A

J. Biol. Chem.

(2002)

E.C. Thrower et al.

A functional interaction between chromogranin B and the inositol 1,4,5-trisphosphate receptor/Ca2+ channel

J. Biol. Chem.

(2003)

A. Maximov et al.

Association of the type 1 inositol (1,4,5)-trisphosphate receptor with 4.1N protein in neurons

Mol. Cell. Neurosci.

(2003)

T.-S. Tang et al.

Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1

Neuron

(2003)

K. Uchida et al.

Critical regions for activation gating of the inositol 1,4,5-trisphosphate receptor

J. Biol. Chem.

(2003)

D.L. Galvan et al.

Carboxyl-terminal sequences critical for inositol 1,4,5-trisphosphate receptor subunit assembly

J. Biol. Chem.

(2002)

S. Zhang et al.

Protein 4.1N Is required for translocation of inositol 1,4,5-trisphosphate receptor type 1 to the basolateral membrane domain in polarized madin-Darby canine kidney cells

J. Biol. Chem.

(2003)

K. Fukatsu et al.

Lateral diffusion of inositol 1,4,5-trisphosphate receptor type 1 is regulated by actin filaments and 4.1N in neuronal dendrites

J. Biol. Chem.

(2004)

Cited by (192)

Expanded polyQ aggregates interact with sarco-endoplasmic reticulum calcium ATPase and Drosophila inhibitor of apoptosis protein1 to regulate polyQ mediated neurodegeneration in Drosophila
2023, Molecular and Cellular Neuroscience
Polyglutamine (polyQ) induced neurodegeneration is one of the leading causes of progressive neurodegenerative disorders characterized clinically by deteriorating movement defects, psychiatric disability, and dementia. Calcium [Ca²⁺] homeostasis, which is essential for the functioning of neuronal cells, is disrupted under these pathological conditions. In this paper, we simulated Huntington's disease phenotype in the neuronal cells of the Drosophila eye and identified [Ca²⁺] pump, sarco-endoplasmic reticulum calcium ATPase (SERCA), as one of the genetic modifiers of the neurodegenerative phenotype. This paper shows genetic and molecular interaction between polyglutamine (polyQ) aggregates, SERCA and DIAP1. We present evidence that polyQ aggregates interact with SERCA and alter its dynamics, resulting in a decrease in cytosolic [Ca²⁺] and an increase in ER [Ca²⁺], and thus toxicity. Downregulating SERCA lowers the enhanced calcium levels in the ER and rescues, morphological and functional defects caused due to expanded polyQ repeats. Cell proliferation markers such as Yorkie (Yki), Scalloped (Sd), and phosphatidylinositol 3 kinases/protein kinase B (PI3K/Akt), also respond to varying levels of calcium due to genetic manipulations, adding to the amelioration of degeneration. These results imply that neurodegeneration due to expanded polyQ repeats is sensitive to SERCA activity, and its manipulation can be an important step toward its therapeutic measures.
Potential role of IP3/Ca<sup>2+</sup> signaling and phosphodiesterases: Relevance to neurodegeneration in Alzheimer's disease and possible therapeutic strategies
2022, Biochemical Pharmacology
Despite large investments by industry and governments, no disease-modifying medications for the treatment of patients with Alzheimer's disease (AD) have been found. The failures of various clinical trials indicate the need for a more in-depth understanding of the pathophysiology of AD and for innovative therapeutic strategies for its treatment. Here, we review the rational for targeting IP3 signaling, cytosolic calcium dysregulation, phosphodiesterases (PDEs), and secondary messengers like cGMP and cAMP, as well as their correlations with the pathophysiology of AD. Various drugs targeting these signaling cascades are still in pre-clinical and clinical trials which support the ideas presented in this article. Further, we describe different molecular mechanisms and medications currently being used in various pre-clinical and clinical trials involving IP3/Ca⁺² signaling. We also highlight various isoforms, as well as the functions and pharmacology of the PDEs broadly expressed in different parts of the brain and attempt to unravel the potential benefits of PDE inhibitors for use as novel medications to alleviate the pathogenesis of AD.
High rates of calcium-free diffusion in the cytosol of living cells
2021, Biophysical Journal
Calcium (Ca²⁺) is a universal second messenger that participates in the regulation of innumerous physiological processes. The way in which local elevations of the cytosolic Ca²⁺ concentration spread in space and time is key for the versatility of the signals. Ca²⁺ diffusion in the cytosol is hindered by its interaction with proteins that act as buffers. Depending on the concentrations and the kinetics of the interactions, there is a large range of values at which Ca²⁺ diffusion can proceed. Having reliable estimates of this range, particularly of its highest end, which corresponds to the ions free diffusion, is key to understand how the signals propagate. In this work, we present the first experimental results with which the Ca²⁺-free diffusion coefficient is directly quantified in the cytosol of living cells. By means of fluorescence correlation spectroscopy experiments performed in Xenopus laevis oocytes and in cells of Saccharomyces cerevisiae, we show that the ions can freely diffuse in the cytosol at a higher rate than previously thought.
The acidocalcisome inositol-1,4,5-trisphosphate receptor of Trypanosoma brucei is stimulated by luminal polyphosphate hydrolysis products
2019, Journal of Biological Chemistry
Acidocalcisomes are acidic calcium stores rich in polyphosphate (polyP) and are present in trypanosomes and also in a diverse range of other organisms. Ca²⁺ is released from these organelles through a channel, inositol 1,4,5-trisphosphate receptor (TbIP₃R), which is essential for growth and infectivity of the parasite Trypanosoma brucei. However, the mechanism by which TbIP₃R controls Ca²⁺ release is unclear. In this work, we expressed TbIP₃R in a chicken B lymphocyte cell line in which the genes for all three vertebrate IP₃Rs were stably ablated (DT40–3KO). We show that IP₃-mediated Ca²⁺ release depends on Ca²⁺ but not on ATP concentration and is inhibited by heparin, caffeine, and 2-aminomethoxydiphenyl borate (2-APB). Excised patch clamp recordings from nuclear membranes of DT40 cells expressing only TbIP₃R disclosed that luminal inorganic orthophosphate (P_i) or pyrophosphate (PP_i), and neutral or alkaline pH can stimulate IP₃-generated currents. In contrast, polyP or acidic pH did not induce these currents, and nuclear membranes obtained from cells expressing rat IP₃R were unresponsive to polyP or its hydrolysis products. Our results are consistent with the notion that polyP hydrolysis products within acidocalcisomes or alkalinization of their luminal pH activate TbIP₃R and Ca²⁺ release. We conclude that TbIP₃R is well-adapted to its role as the major Ca²⁺ release channel of acidocalcisomes in T. brucei.
Differential regulation of ion channels function by proteolysis
2018, Biochimica et Biophysica Acta - Molecular Cell Research
Citation Excerpt :
All three isoforms of IP3R are substrates of proteases. Early in vitro studies investigating IP3R domain structure demonstrated that exposure of R1 to low concentrations of trypsin resulted in five predictable and reproducible receptor fragments (Fig. 2A/B) [57–59]. These data were interpreted to indicate that R1 comprises five compact globular domains, interconnected by four solvent exposed linker regions.
Ion channels are pore-forming protein complexes in membranes that play essential roles in a diverse array of biological activities. Ion channel activity is strictly regulated at multiple levels and by numerous cellular events to selectively activate downstream effectors involved in specific biological activities. For example, ions, binding proteins, nucleotides, phosphorylation, the redox state, channel subunit composition have all been shown to regulate channel activity and subsequently allow channels to participate in distinct cellular events. While these forms of modulation are well documented and have been extensively reviewed, in this article, we will first review and summarize channel proteolysis as a novel and quite widespread mechanism for altering channel activity. We will then highlight the recent findings demonstrating that proteolysis profoundly alters Inositol 1,4,5 trisphosphate receptor activity, and then discuss its potential functional ramifications in various developmental and pathological conditions.
Regulation of bile secretion by calcium signaling in health and disease
2018, Biochimica et Biophysica Acta - Molecular Cell Research
Calcium (Ca²⁺) signaling controls secretion in many types of cells and tissues. In the liver, Ca²⁺ regulates secretion in both hepatocytes, which are responsible for primary formation of bile, and cholangiocytes, which line the biliary tree and further condition the bile before it is secreted. Cholestatic liver diseases, which are characterized by impaired bile secretion, may result from impaired Ca²⁺ signaling mechanisms in either hepatocytes or cholangiocytes. This review will discuss the Ca²⁺ signaling machinery and mechanisms responsible for regulation of secretion in both hepatocytes and cholangiocytes, and the pathophysiological changes in Ca²⁺ signaling that can occur in each of these cell types to result in cholestasis.

View all citing articles on Scopus

View full text

The inositol 1,4,5-trisphosphate receptors

Abstract

Introduction

Section snippets

InsP3R1

InsP3R2 and InsP3R3

DmInsP3R and CeInsP3R

Future directions

Acknowledgments

Curr. Opin. Neurobiol.

J. Biol. Chem.

Mol. Cell

Neuron

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biophys. J.

Brain Res. Mol. Brain Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Neuron

Cell

J. Biol. Chem.

FEBS Lett.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Cell Calcium

J. Biol. Chem.

J. Biol. Chem.

Biophys. J.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biophys. J.

Biophys. J.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell. Neurosci.

Neuron

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

InsP₃R1

InsP₃R2 and InsP₃R3

DmInsP₃R and CeInsP₃R