Ryanodine-Inositol 1,4,5-triphosphate receptor calcium channels

Last updated
Ryanodine receptor 2
Identifiers
SymbolRYR2
Pfam PF02026
InterPro IPR003032
SMART SM00054
PROSITE PS50188
TCDB 1.A.3
OPM superfamily 8
OPM protein 6dr2
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 4JKQ

The ryanodine-inositol 1,4,5-triphosphate receptor Ca2+ channel (RIR-CaC) family includes Ryanodine receptors and Inositol trisphosphate receptors. Members of this family are large proteins, some exceeding 5000 amino acyl residues in length. This family belongs to the Voltage-gated ion channel (VIC) superfamily. Ry receptors occur primarily in muscle cell sarcoplasmic reticular (SR) membranes, and IP3 receptors occur primarily in brain cell endoplasmic reticular (ER) membranes where they effect release of Ca2+ into the cytoplasm upon activation (opening) of the channel. They are redox sensors, possibly providing a partial explanation for how they control cytoplasmic Ca2+. Ry receptors have been identified in heart mitochondria where they provide the main pathway for Ca2+ entry. [1] Sun et al. (2011) have demonstrated oxygen-coupled redox regulation of the skeletal muscle ryanodine receptor-Ca2+ release channel (RyR1;TC# 1.A.3.1.2) by NADPH oxidase 4. [2]

Contents

Function

Ryanodine (Ry)-sensitive and inositol 1,4,5-triphosphate (IP3)-sensitive Ca2+-release channels function in the release of Ca2+ from intracellular storage sites in animal cells and thereby regulate various Ca2+-dependent physiological processes. [3] The Ry receptors are activated as a result of the activity of dihydropyridine-sensitive Ca2+ channels. Ry receptors, IP3 receptors, and dihydropyridine-sensitive Ca2+ channels (TC#1.A.1.11.2) are members of the voltage-sensitive ion channel (VIC) superfamily (TC# 1.A.1). Dihydropyridine-sensitive channels are present in the T-tubular systems of muscle tissues. Ry receptor 2 dysfunction leads to arrhythmias, altered myocyte contraction during the process of EC (excitation-contraction) coupling, and sudden cardiac death. [4] Neomycin is a RyR blocker which serves as a pore plug and a competitive antagonist at a cytoplasmic Ca2+ binding site that causes allosteric inhibition. [5]

The generalized transport reaction catalyzed by members of the RIR-CaC family following channel activation is: [6]

Ca2+ (out, or sequestered in the ER or SR) → Ca2+ (cell cytoplasm).

Structure

Ry and IP3 receptors consist of (1) an N-terminal ligand binding domain, (2) a central modulatory domain and (3) a C-terminal channel-forming domain. The 3-D structure (2.2 Å) of the inositol 1,3,5-triphosphate receptor of an IP3 receptor has been solved ( PDB: 1N4K ​). [7] Structural and functional conservation of key domains in IP3 and ryanodine receptors has been reviewed by Seo et al. (2012). [8] Members of the VIC (TC# 1.A.1), RIR-CaC (TC# 2.A.3) and TRP-CC (TC# 1.A.4) families have similar transmembrane domain structures, but very different cytosolic domain structures. [9]

The channel domains of the Ry and IP3 receptors comprise a coherent family that shows apparent structural similarities as well as sequence similarity with proteins of the VIC family (TC #1.A.1). The Ry receptors and the IP3 receptors cluster separately on the RIR-CaC family tree. They both have homologues in Drosophila . Based on the phylogenetic tree for the family, the family probably evolved in the following sequence:

  1. A gene duplication event occurred that gave rise to Ry and IP3 receptors in invertebrates.
  2. Vertebrates evolved from invertebrates.
  3. The three isoforms of each receptor arose as a result of two distinct gene duplication events.
  4. These isoforms were transmitted to mammals before divergence of the mammalian species.

Ry receptors

Ry receptors are homotetrameric complexes with each subunit exhibiting a molecular size of over 500,000 daltons (about 5,000 amino acyl residues). They possess C-terminal domains with six putative transmembrane α-helical spanners (TMSs). Putative pore-forming sequences occur between the fifth and sixth TMSs as suggested for members of the VIC family. Recently an 8 TMS topology with four hairpin loops has been suggested. [10] The large N-terminal hydrophilic domains and the small C-terminal hydrophilic domains are localized to the cytoplasm. Mammals possess at least three isoforms which probably arose by gene duplication and divergence before divergence of the mammalian species. Homologues are present in Drosophila melanogaster and Caenorabditis elegans .

Tetrameric cardiac and skeletal muscle sarcoplasmic reticular ryanodine receptors (RyR) are large (~2.3 MDa). The complexes include signaling proteins such as 4 FKBP12 molecules, protein kinases, phosphatases, etc. They modulate the activity of and the binding of immunophilin to the channel. FKBP12 is required for normal gating as well as coupled gating between neighboring channels. PKA phosphorylation of RyR dissociates FKBP12 yielding increased Ca2+ sensitivity for activation, part of the excitation-contraction (fight or flight) response. [11]

IP3 receptors

IP3 receptors resemble Ry receptors in many respects. [12]

  1. They are homotetrameric complexes with each subunit exhibiting a molecular size of over 300,000 daltons (about 2,700 amino acyl residues).
  2. They possess C-terminal channel domains that are homologous to those of the Ry receptors.
  3. The channel domains possess six putative TMSs and a putative channel lining region between TMSs 5 and 6.
  4. Both the large N-terminal domains and the smaller C-terminal tails face the cytoplasm.
  5. They possess covalently linked carbohydrate on extracytoplasmic loops of the channel domains.
  6. They have three currently recognized isoforms (types 1, 2, and 3) in mammals which are subject to differential regulation and have different tissue distributions. They co-localize with Orai channels (TC# 1.A.52) in pancreatic acinar cells. [13]

IP3 receptors possess three domains:

  1. N-terminal IP3-binding domains,
  2. central coupling or
  3. regulatory domains and C-terminal channel domains.

Channels are activated by IP3 binding, and like the Ry receptors, the activities of the IP3 receptor channels are regulated by phosphorylation of the regulatory domains, catalyzed by various protein kinases. They predominate in the endoplasmic reticular membranes of various cell types in the brain but have also been found in the plasma membranes of some nerve cells derived from a variety of tissues.

Specific residues in the putative pore helix, selectivity filter and S6 transmembrane helix of the IP3 receptor, have been mutated in order to examine their effects on channel function. [14] Mutation of 5 of 8 highly conserved residues in the pore helix/selectivity filter region inactivated the channel. Channel function was also inactivated by G2586P and F2592D mutations. These studies defined the pore-forming segment in IP3. [14]

See also

Related Research Articles

Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the plasma membrane, by phospholipase C (PLC). Together with diacylglycerol (DAG), IP3 is a second messenger molecule used in signal transduction in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell, where it binds to its receptor, which is a calcium channel located in the endoplasmic reticulum. When IP3 binds its receptor, calcium is released into the cytosol, thereby activating various calcium regulated intracellular signals.

<span class="mw-page-title-main">Sarcoplasmic reticulum</span> Menbrane-bound structure in muscle cells for storing calcium

The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kept relatively constant, with the concentration of calcium ions within a cell being 10,000 times smaller than the concentration of calcium ions outside the cell. This means that small increases in calcium ions within the cell are easily detected and can bring about important cellular changes (the calcium is said to be a second messenger). Calcium is used to make calcium carbonate (found in chalk) and calcium phosphate, two compounds that the body uses to make teeth and bones. This means that too much calcium within the cells can lead to hardening (calcification) of certain intracellular structures, including the mitochondria, leading to cell death. Therefore, it is vital that calcium ion levels are controlled tightly, and can be released into the cell when necessary and then removed from the cell.

<span class="mw-page-title-main">Inositol trisphosphate receptor</span> Class of transport proteins

Inositol trisphosphate receptor (InsP3R) is a membrane glycoprotein complex acting as a Ca2+ channel activated by inositol trisphosphate (InsP3). InsP3R is very diverse among organisms, and is necessary for the control of cellular and physiological processes including cell division, cell proliferation, apoptosis, fertilization, development, behavior, learning and memory. Inositol triphosphate receptor represents a dominant second messenger leading to the release of Ca2+ from intracellular store sites. There is strong evidence suggesting that the InsP3R plays an important role in the conversion of external stimuli to intracellular Ca2+ signals characterized by complex patterns relative to both space and time, such as Ca2+ waves and oscillations.

<span class="mw-page-title-main">Ligand-gated ion channel</span> Type of ion channel transmembrane protein

Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+-Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.

Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons. There are three major isoforms of the ryanodine receptor, which are found in different tissues and participate in different signaling pathways involving calcium release from intracellular organelles. The RYR2 ryanodine receptor isoform is the major cellular mediator of calcium-induced calcium release (CICR) in animal cells.

The formyl peptide receptors (FPR) belong to a class of G protein-coupled receptors involved in chemotaxis. In humans, there are three formyl peptide receptor isoforms, each encoded by a separate gene that are named FPR1, FPR2, and FPR3. These receptors were originally identified by their ability to bind N-formyl peptides such as N-formylmethionine produced by the degradation of either bacterial or host cells. Hence formyl peptide receptors are involved in mediating immune cell response to infection. These receptors may also act to suppress the immune system under certain conditions. The close phylogenetic relation of signaling in chemotaxis and olfaction was recently proved by detection formyl peptide receptor like proteins as a distinct family of vomeronasal organ chemosensors in mice.

<span class="mw-page-title-main">FKBP1A</span> Protein and coding gene in humans

Peptidyl-prolyl cis-trans isomerase FKBP1A is an enzyme that in humans is encoded by the FKBP1A gene. It is also commonly referred to as FKBP-12 or FKBP12 and is a member of a family of FK506-binding proteins (FKBPs).

<span class="mw-page-title-main">ITPR1</span> Protein-coding gene in the species Homo sapiens

Inositol 1,4,5-trisphosphate receptor type 1 is a protein that in humans is encoded by the ITPR1 gene.

<span class="mw-page-title-main">Ryanodine receptor 2</span> Transport protein and coding gene in humans

Ryanodine receptor 2 (RYR2) is one of a class of ryanodine receptors and a protein found primarily in cardiac muscle. In humans, it is encoded by the RYR2 gene. In the process of cardiac calcium-induced calcium release, RYR2 is the major mediator for sarcoplasmic release of stored calcium ions.

Ca<sub>v</sub>1.1 Mammalian protein found in Homo sapiens

Cav1.1 also known as the calcium channel, voltage-dependent, L type, alpha 1S subunit, (CACNA1S), is a protein which in humans is encoded by the CACNA1S gene. It is also known as CACNL1A3 and the dihydropyridine receptor.

<span class="mw-page-title-main">FKBP1B</span> Protein-coding gene in the species Homo sapiens

Peptidyl-prolyl cis-trans isomerase FKBP1B is an enzyme that in humans is encoded by the FKBP1B gene.

<span class="mw-page-title-main">Ryanodine receptor 1</span> Protein and coding gene in humans

Ryanodine receptor 1 (RYR-1) also known as skeletal muscle calcium release channel or skeletal muscle-type ryanodine receptor is one of a class of ryanodine receptors and a protein found primarily in skeletal muscle. In humans, it is encoded by the RYR1 gene.

Ankyrin-2, also known as Ankyrin-B, and Brain ankyrin, is a protein which in humans is encoded by the ANK2 gene. Ankyrin-2 is ubiquitously expressed, but shows high expression in cardiac muscle. Ankyrin-2 plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in cardiomyocytes, as well as in costamere structures. Mutations in ANK2 cause a dominantly-inherited, cardiac arrhythmia syndrome known as long QT syndrome 4 as well as sick sinus syndrome; mutations have also been associated to a lesser degree with hypertrophic cardiomyopathy. Alterations in ankyrin-2 expression levels are observed in human heart failure.

<span class="mw-page-title-main">ITPR3</span> Protein-coding gene in the species Homo sapiens

Inositol 1,4,5-trisphosphate receptor, type 3, also known as ITPR3, is a protein which in humans is encoded by the ITPR3 gene. The protein encoded by this gene is both a receptor for inositol triphosphate and a calcium channel.

<span class="mw-page-title-main">Ryanodine receptor 3</span> Transport protein and coding gene in humans

Ryanodine receptor 3 is one of a class of ryanodine receptors and a protein that in humans is encoded by the RYR3 gene. The protein encoded by this gene is both a calcium channel and a receptor for the plant alkaloid ryanodine. RYR3 and RYR1 control the resting calcium ion concentration in skeletal muscle.

Imperatoxin I (IpTx) is a peptide toxin derived from the venom of the African scorpion Pandinus imperator.

JTV-519 (K201) is a 1,4-benzothiazepine derivative that interacts with many cellular targets. It has many structural similarities to diltiazem, a Ca2+ channel blocker used for treatment of hypertension, angina pectoris and some types of arrhythmias. JTV-519 acts in the sarcoplasmic reticulum (SR) of cardiac myocytes by binding to and stabilizing the ryanodine receptor (RyR2) in its closed state. It can be used in the treatment of cardiac arrhythmias, heart failure, catecholaminergic polymorphic ventricular tachycardia (CPVT) and store overload-induced Ca2+ release (SOICR). Currently, this drug has only been tested on animals and its side effects are still unknown. As research continues, some studies have also found a dose-dependent response; where there is no improvement seen in failing hearts at 0.3 μM and a decline in response at 1 μM.

The transient receptor potential Ca2+ channel (TRP-CC) family (TC# 1.A.4) is a member of the voltage-gated ion channel (VIC) superfamily and consists of cation channels conserved from worms to humans. The TRP-CC family also consists of seven subfamilies (TRPC, TRPV, TRPM, TRPN, TRPA, TRPP, and TRPML) based on their amino acid sequence homology:

  1. the canonical or classic TRPs,
  2. the vanilloid receptor TRPs,
  3. the melastatin or long TRPs,
  4. ankyrin (whose only member is the transmembrane protein 1 [TRPA1])
  5. TRPN after the nonmechanoreceptor potential C (nonpC), and the more distant cousins,
  6. the polycystins
  7. and mucolipins.

The testis-enhanced gene transcript (TEGT) family includes the testis-enhanced gene transcript proteins of mammals, which are expressed at high levels in the testis, the putative glutamate/aspartate binding proteins of plants and animals, the YccA protein of Escherichia coli and the YetJ protein of Bacillus subtilis. These proteins are about 200-250 residues in length and exhibit 7 TMSs.

References

  1. ↑ Beutner G, Sharma VK, Giovannucci DR, Yule DI, Sheu SS (June 2001). "Identification of a ryanodine receptor in rat heart mitochondria". The Journal of Biological Chemistry. 276 (24): 21482–8. doi:10.1074/jbc.M101486200. PMID   11297554.
  2. ↑ Sun QA, Hess DT, Nogueira L, Yong S, Bowles DE, Eu J, Laurita KR, Meissner G, Stamler JS (September 2011). "Oxygen-coupled redox regulation of the skeletal muscle ryanodine receptor-Ca2+ release channel by NADPH oxidase 4". Proceedings of the National Academy of Sciences of the United States of America. 108 (38): 16098–103. Bibcode:2011PNAS..10816098S. doi: 10.1073/pnas.1109546108 . PMC   3179127 . PMID   21896730.
  3. ↑ Santulli, Gaetano; Marks, Andrew (2015). "Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging". Current Molecular Pharmacology. 8 (2): 206–222. doi:10.2174/1874467208666150507105105. ISSN   1874-4672. PMID   25966694.
  4. ↑ Thomas NL, George CH, Williams AJ, Lai FA (November 2007). "Ryanodine receptor mutations in arrhythmias: advances in understanding the mechanisms of channel dysfunction". Biochemical Society Transactions. 35 (Pt 5): 946–51. doi:10.1042/BST0350946. PMID   17956252.
  5. ↑ Laver DR, Hamada T, Fessenden JD, Ikemoto N (December 2007). "The ryanodine receptor pore blocker neomycin also inhibits channel activity via a previously undescribed high-affinity Ca(2+) binding site". The Journal of Membrane Biology. 220 (1–3): 11–20. doi:10.1007/s00232-007-9067-3. PMID   17879109. S2CID   38255566.
  6. ↑ "1.A.3 The Ryanodine-Inositol 1,4,5-triphosphate Receptor Ca2+ Channel (RIR-CaC) Family". TCDB. Retrieved 2016-04-10.
  7. ↑ Bosanac I, Alattia JR, Mal TK, Chan J, Talarico S, Tong FK, Tong KI, Yoshikawa F, Furuichi T, Iwai M, Michikawa T, Mikoshiba K, Ikura M (December 2002). "Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand". Nature. 420 (6916): 696–700. Bibcode:2002Natur.420..696B. doi:10.1038/nature01268. PMID   12442173. S2CID   4422308.
  8. ↑ Seo MD, Velamakanni S, Ishiyama N, Stathopulos PB, Rossi AM, Khan SA, Dale P, Li C, Ames JB, Ikura M, Taylor CW (January 2012). "Structural and functional conservation of key domains in InsP3 and ryanodine receptors". Nature. 483 (7387): 108–12. Bibcode:2012Natur.483..108S. doi:10.1038/nature10751. PMC   3378505 . PMID   22286060.
  9. ↑ Mio K, Ogura T, Sato C (May 2008). "Structure of six-transmembrane cation channels revealed by single-particle analysis from electron microscopic images". Journal of Synchrotron Radiation. 15 (Pt 3): 211–4. doi:10.1107/S0909049508004640. PMC   2394823 . PMID   18421141.
  10. ↑ Du GG, Sandhu B, Khanna VK, Guo XH, MacLennan DH (December 2002). "Topology of the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum (RyR1)". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16725–30. Bibcode:2002PNAS...9916725D. doi: 10.1073/pnas.012688999 . PMC   139211 . PMID   12486242.
  11. ↑ Gaburjakova M, Gaburjakova J, Reiken S, Huang F, Marx SO, Rosemblit N, Marks AR (May 2001). "FKBP12 binding modulates ryanodine receptor channel gating". The Journal of Biological Chemistry. 276 (20): 16931–5. doi: 10.1074/jbc.M100856200 . PMID   11279144.
  12. ↑ Mikoshiba, Katsuhiko; Furuichi, Teiichi; Miyawaki, Atsushi (1997-01-01). "IP3-sensitive calcium channel". In Lee, A. G. (ed.). Transmembrane Receptors and Channels. Transmembrane Receptors and Channels. Vol. 6. JAI. pp. 273–289. doi:10.1016/s1874-5342(96)80040-7. ISBN   9781559386630.
  13. ↑ Lur G, Sherwood MW, Ebisui E, Haynes L, Feske S, Sutton R, Burgoyne RD, Mikoshiba K, Petersen OH, Tepikin AV (June 2011). "InsP₃receptors and Orai channels in pancreatic acinar cells: co-localization and its consequences". The Biochemical Journal. 436 (2): 231–9. doi:10.1042/BJ20110083. PMC   3262233 . PMID   21568942.
  14. 1 2 Schug ZT, da Fonseca PC, Bhanumathy CD, Wagner L, Zhang X, Bailey B, Morris EP, Yule DI, Joseph SK (February 2008). "Molecular characterization of the inositol 1,4,5-trisphosphate receptor pore-forming segment". The Journal of Biological Chemistry. 283 (5): 2939–48. doi: 10.1074/jbc.M706645200 . PMID   18025085.

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