1.A.3 The Ryanodine-Inositol 1,4,5-triphosphate Receptor Ca2+ Channel (RIR-CaC) Family

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 (Van Petegem 2012). They 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 (Bosanac et al., 2002). Structural and functional conservation of key domains in InsP(3) and ryanodine receptors has been reviewed (Seo et al., 2012).  Members of the VIC (1.A.1), RIR-CaC (2.A.3) and TRP-CC (1.A.4) families have similar transmembrane domain structures, but very different cytosolic doman structures (Mio et al. 2008). Ryanodine receptor regulation occurs by intramolecular interaction between cytoplasmic and transmembrane domains (George et al. 2004).

RyR1 activation is regulated by several proteins from both the cytoplasm and lumen of the SR. Chen and Kudryashev 2020 reported the structure of RyR1 (TC# 1.A.3.1.2) from native SR membranes in closed and open states. Compared to previously reported structures of purified RyR1, the new structures reveal helix-like densities traversing the bilayer approximately 5 nm from the RyR1 transmembrane domain and sarcoplasmic extensions linking RyR1 to a putative calsequestrin network. The primary conformation of RyR1 in situ and its structural variations were reported (Chen and Kudryashev 2020). The activation of RyR1 is associated with changes in membrane curvature and movement in the sarcoplasmic extensions. The G4911E mutation in GdRyR may be a potential mechanism for the development of resistance to diamide insecticides in Galeruca daurica (a leaf beetle) (Ren et al. 2022).

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, and these provide the main pathway for Ca2+ entry (Beutner et al., 2001). Sun et al. (2011) have demonstrated oxygen-coupled redox regulation of the skeletal muscle ryanodine receptor-Ca2+ release channel (RyR1) by NADPH oxidase 4.

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, alterred myocyte contraction during the process of EC (excitation-contraction) coupling, and sudden cardiac death (Thomas et al., 2007). 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 (Laver et al., 2007). The cytoplasmic domain of RyR1, which is primarily expressed in skeletal muscle, interacts with Ca2+ and Mg2+ ions, ligands such as ATP, caffeine and ryanodine, and accessory proteins such as calmodulin (CaM; TC# 8.A.82) (Chen and Kudryashev 2020). CaM in its Ca2+-unbound form is a weak agonist of RyR1, while in its Ca2+-bound form it is an RyR1 antagonist. A 10-kDa protein, S100A1, capable of increasing the open probability of RyR1, may compete with CaM for the same binding site on the receptor. In the SR lumen, the major Ca2+-buffering protein, calsequestrin (CSQ; TC# 8.A.88), interacts with RyR1 indirectly through the membrane-anchored proteins triadin TC# 8.A.28.1.3) and junctin (TC# 8.A.28.1.4), each of which has a single TMS and a disordered intra-SR domain. CSQ has two isoforms: CSQ1, which interacts with RyR1 in skeletal muscle, and CSQ2, which interacts with RyR2, a form primarily expressed in cardiac muscle. CSQ polymerizes in a Ca2+-dependent manner and regulates the activity of RyR1. Biochemical analysis suggests that CSQ1 is the major protein component found in the sarcoplasmic reticulum at its junction with T-tubules (Chen and Kudryashev 2020).

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 (Du et al., 2002). The large N-terminal hydrophilic domains and the small C-terminal hydrophilic domains are localized to the cytoplasm. Low resolution 3-dimensional structural data are available. 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. Interactions of RyRs with insecticides and drugs has been reviewed (Sun and Xu 2019).

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 (Gaburjakova et al., 2001).

RyR1 (TC# 1.A.3.1.2) is an intracellular calcium (Ca2+) release channel required for skeletal muscle contraction. des Georges et al. 2016 presented cryo-EM reconstructions of RyR1 in multiple functional states, revealing the structural basis of channel gating and ligand-dependent activation. Binding sites for the channel activators Ca2+, ATP, and caffeine were identified at interdomain interfaces of the C-terminal domain. Either ATP or Ca2+ alone induces conformational changes in the cytoplasmic assembly ('priming'), without pore dilation. In contrast, in the presence of all three activating ligands, high-resolution reconstructions of open and closed states of RyR1 were obtained from the same sample, enabling analyses of conformational changes associated with gating. Gating involves global conformational changes in the cytosolic assembly accompanied by local changes in the transmembrane domain, which include bending of the S6 transmembrane segment and consequent pore dilation, displacement, and deformation of the S4-S5 linker and conformational changes in the pseudo-voltage-sensor domain (des Georges et al. 2016).

IP3 receptors resemble Ry receptors in many respects (Mikoshiba, 2012). (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 (1.A.52) in pancreatic acinar cells (Lur et al., 2011).

IP3 receptors possess three domains: N-terminal IP3-binding domains, central coupling or 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 (Schug et al., 2008) in order to examine their effects on channel function. 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 IP (Schug et al., 2008).

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. 

In the heart, electrical stimulation of cardiac myocytes increases the open probability of sarcolemmal voltage-sensitive Ca2+ channels and the flux of Ca2+ into the cells. This increases Ca2+ binding to ryanodine receptors (RyR2). Their openings cause cell-wide release of Ca2+, which in turn causes muscle contraction and the generation of the mechanical force required to pump blood. In resting myocytes, RyR2s can also open spontaneously giving rise to spatially-confined Ca2+ release events known as 'sparks.' RyR2s are organized in a lattice to form clusters in the junctional sarcoplasmic reticulum membrane. Walker et al. 2016 demonstrated that the spatial arrangement of RyR2s within clusters strongly influences the frequency of Ca2+ sparks. They showed that the probability of a Ca2+ spark occurring when a single RyR2 in the cluster opens spontaneously can be predicted from the precise spatial arrangements of the RyR2s. 

Large-conductance Ca2+ release channels, ryanodine receptors (RyRs), mediate the release of Ca2+ from the endo/sarcoplasmic reticulum, to the cytoplasm. There are three mammalian RyR isoforms: RyR1 is present in skeletal muscle; RyR2 is in heart muscle; and RyR3 is expressed at low levels in many tissues including the brain, smooth muscle, and slow-twitch skeletal muscle. RyRs form large protein complexes comprising four 560-kD RyR subunits, four approximately 12-kD FK506-binding proteins, and various accessory proteins including calmodulin, protein kinases, and protein phosphatases (Meissner 2017). The greatest sequence similarity amoung RyRs is in the C-terminal region that forms the transmembrane, ion-conducting domain of ~500 aas. The remaining approximately 4,500 aas form the large regulatory cytoplasmic 'foot' structure. Experimental evidence for Ca2+, ATP, phosphorylation, and redox-sensitive sites in the cytoplasmic structure have been described. Exogenous effectors include the two Ca2+ releasing agents caffeine and ryanodine (Meissner 2017). 

Diamide insecticides target insect ryanodine receptors (RyRs), causing uncontrolled calcium release from the sarcoplasmic and endoplasmic reticulum. Despite their high potency and species selectivity, several resistance mutations have emerged.  The mode of action of different diamide insecticides and  the molecular mechanism of resistance mutations, provide clues for the development of novel pesticides that can bypass the resistance mutations (Lin et al. 2024).

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

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



This family belongs to the VIC Superfamily.

 

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Subedi, K.P., T.D. Singh, J.C. Kim, and S.H. Woo. (2012). Cloning and expression of a new inositol 1,4,5-trisphosphate receptor type 1 splice variant in adult rat atrial myocytes. Cell Mol Biol Lett 17: 124-135.

Subramanian, M., S. Jayakumar, S. Richhariya, and G. Hasan. (2013). Loss of IP3 receptor function in neuropeptide secreting neurons leads to obesity in adult Drosophila. BMC Neurosci 14: 157.

Sun, L., J. Shay, M. McLoed, K. Roodhouse, S.H. Chung, C.M. Clark, J.K. Pirri, M.J. Alkema, and C.V. Gabel. (2014). Neuron.al regeneration in C. elegans requires subcellular calcium release by ryanodine receptor channels and can be enhanced by optogenetic stimulation. J. Neurosci. 34: 15947-15956.

Sun, Q.A., D.T. Hess, L. Nogueira, S. Yong, D.E. Bowles, J. Eu, K.R. Laurita, G. Meissner, and J.S. Stamler. (2011). Oxygen-coupled redox regulation of the skeletal muscle ryanodine receptor-Ca2+ release channel by NADPH oxidase 4. Proc. Natl. Acad. Sci. USA 108: 16098-16103.

Sun, Z. and H. Xu. (2019). Ryanodine Receptors for Drugs and Insecticides: An Overview. Mini Rev Med Chem 19: 22-33.

Takenaka, M., M. Kodama, T. Murayama, M. Ishigami-Yuasa, S. Mori, R. Ishida, J. Suzuki, K. Kanemaru, M. Sugihara, M. Iino, A. Miura, H. Nishio, S. Morimoto, H. Kagechika, T. Sakurai, and N. Kurebayashi. (2023). Screening for Novel Type 2 Ryanodine Receptor Inhibitors by Endoplasmic Reticulum Ca Monitoring. Mol Pharmacol 104: 275-286.

Tang, Z., Y. Ding, R. Zhang, M. Zhang, Q. Guan, L. Zhang, H. Wang, Y. Chen, R. Jiang, W. Zhang, and J. Wang. (2022). Genetic polymorphisms of Ca transport proteins and molecular chaperones in mitochondria-associated endoplasmic reticulum membrane and non-alcoholic fatty liver disease. Front Endocrinol (Lausanne) 13: 1056283.

Tao, Y., S. Gutteridge, E.A. Benner, L. Wu, D.F. Rhoades, M.D. Sacher, M.A. Rivera, J. Desaeger, and D. Cordova. (2013). Identification of a critical region in the Drosophila ryanodine receptor that confers sensitivity to diamide insecticides. Insect Biochem Mol Biol 43: 820-828.

Thomas, N.L., C.H. George, A.J. Williams, and F.A. Lai. (2007). Ryanodine receptor mutations in arrhythmias: advances in understanding the mechanisms of channel dysfunction. Biochem. Soc. Trans. 35:946-951.

Thomas-Virnig, C.L., P.A. Sims, J.S. Simske, and J. Hardin. (2004). The inositol 1,4,5-trisphosphate receptor regulates epidermal cell migration in Caenorhabditis elegans. Curr. Biol. 14: 1882-1887.

Tolonen, J.P., R. Parolin Schnekenberg, S. McGowan, D. Sims, M. McEntagart, F. Elmslie, D. Shears, H. Stewart, G.K. Tofaris, T. Dabir, P.J. Morrison, D. Johnson, M. Hadjivassiliou, S. Ellard, C. Shaw-Smith, A. Znaczko, A. Dixit, M. Suri, A. Sarkar, R.E. Harrison, G. Jones, H. Houlden, G. Ceravolo, J. Jarvis, J. Williams, M.E. Shanks, P. Clouston, J. Rankin, L. Blumkin, T. Lerman-Sagie, P. Ponger, S. Raskin, K. Granath, J. Uusimaa, H. Conti, E. McCann, S. Joss, A.J.M. Blakes, K. Metcalfe, H. Kingston, M. Bertoli, R. Kneen, S.A. Lynch, I. Martínez Albaladejo, A.P. Moore, W.D. Jones, , E.B.E. Becker, and A.H. Németh. (2023). Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design. Mov Disord. [Epub: Ahead of Print]

Troczka, B.J., A.J. Williams, C. Bass, M.S. Williamson, L.M. Field, and T.G. Davies. (2015). Molecular cloning, characterisation and mRNA expression of the ryanodine receptor from the peach-potato aphid, Myzus persicae. Gene 556: 106-112.

Troczka, B.J., M.S. Williamson, L.M. Field, and T.G.E. Davies. (2017). Rapid selection for resistance to diamide insecticides in Plutella xylostella via specific amino acid polymorphisms in the ryanodine receptor. Neurotoxicology 60: 224-233.

Tunwell, R.E.A., C. Wickenden, B.M.A. Bertrand, V.I. Shevchenko, M.B. Walsh, P.D. Allen and F.A. Lai (1996). The human cardiac muscle ryanodine receptor-calcium release channel: identification, primary structure and topological analysis. Biochem. J. 318: 477-487.

Van Petegem, F. (2012). Ryanodine receptors: structure and function. J. Biol. Chem. 287: 31624-31632.

Walker, D.S., N.J. Gower, S. Ly, G.L. Bradley, and H.A. Baylis. (2002). Regulated disruption of inositol 1,4,5-trisphosphate signaling in Caenorhabditis elegans reveals new functions in feeding and embryogenesis. Mol. Biol. Cell 13: 1329-1337.

Walker, D.S., R.P. Vázquez-Manrique, N.J. Gower, E. Gregory, W.R. Schafer, and H.A. Baylis. (2009). Inositol 1,4,5-trisphosphate signalling regulates the avoidance response to nose touch in Caenorhabditis elegans. PLoS Genet 5: e1000636.

Walker, M.A., T. Kohl, S.E. Lehnart, J.L. Greenstein, W.J. Lederer, and R.L. Winslow. (2015). On the Adjacency Matrix of RyR2 Cluster Structures. PLoS Comput Biol 11: e1004521.

Wang, K.Y., X.Z. Jiang, G.R. Yuan, F. Shang, and J.J. Wang. (2015). Molecular Characterization, mRNA Expression and Alternative Splicing of Ryanodine Receptor Gene in the Brown Citrus Aphid, Toxoptera citricida (Kirkaldy). Int J Mol Sci 16: 15220-15234.

Wei, R., X. Wang, Y. Zhang, S. Mukherjee, L. Zhang, Q. Chen, X. Huang, S. Jing, C. Liu, S. Li, G. Wang, Y. Xu, S. Zhu, A.J. Williams, F. Sun, and C.C. Yin. (2016). Structural insights into Ca2+-activated long-range allosteric channel gating of RyR1. Cell Res 26: 977-994.

Wheeler, G.L. and C. Brownlee. (2008). Ca2+ signalling in plants and green algae--changing channels. Trends Plant Sci. 13: 506-514.

Wu, S., F. Wang, J. Huang, Q. Fang, Z. Shen, and G. Ye. (2013). Molecular and cellular analyses of a ryanodine receptor from hemocytes of Pieris rapae. Dev Comp Immunol 41: 1-10.

Wu, S.F., D.D. Zhao, J.M. Huang, S.Q. Zhao, L.Q. Zhou, and C.F. Gao. (2018). Molecular characterization and expression profiling of ryanodine receptor gene in the pink stem borer, Sesamia inferens (Walker). Pestic Biochem Physiol 146: 1-6.

Xia, R., T. Stangler and J.J. Abramson (2000). Skeletal muscle ryanodine receptor is a redox sensor with a well defined redox potential that is sensitive to channel modulators. J. Biol. Chem. 275: 36556-36561.

Xu, L., D.D. Mowrey, V.R. Chirasani, Y. Wang, D.A. Pasek, N.V. Dokholyan, and G. Meissner. (2017). G4941K substitution in the pore-lining S6 helix of the skeletal muscle ryanodine receptor increases RyR1 sensitivity to cytosolic and luminal Ca2. J. Biol. Chem. [Epub: Ahead of Print]

Xu, L., Y. Wang, N. Yamaguchi, D.A. Pasek, and G. Meissner. (2008). Single channel properties of heterotetrameric mutant RyR1 ion channels linked to core myopathies. J. Biol. Chem. 283: 6321-6329.

Yamada, Y., J. Iemura, A. Kambara, N. Tateishi, Y. Kozaki, M. Yamada, J. Maruyama, and E. Azuma. (2023). Association of postoperative atrial fibrillation with higher dosing ratios of protamine-to-heparin. J Extra Corpor Technol 55: 23-29.

Yuan, G.R., K.Y. Wang, X. Mou, R.Y. Luo, W. Dou, and J.J. Wang. (2017). Molecular cloning, mRNA expression and alternative splicing of a ryanodine receptor gene from the citrus whitefly, Dialeurodes citri (Ashmead). Pestic Biochem Physiol 142: 59-66.

Yuan, G.R., W.Z. Shi, W.J. Yang, X.Z. Jiang, W. Dou, and J.J. Wang. (2014). Molecular characteristics, mRNA expression, and alternative splicing of a ryanodine receptor gene in the oriental fruit fly, Bactrocera dorsalis (Hendel). PLoS One 9: e95199.

Zalk, R. and A.R. Marks. (2017). Ca2+ Release Channels Join the ''Resolution Revolution''. Trends. Biochem. Sci. [Epub: Ahead of Print]

Zalk, R., O.B. Clarke, A. des Georges, R.A. Grassucci, S. Reiken, F. Mancia, W.A. Hendrickson, J. Frank, and A.R. Marks. (2015). Structure of a mammalian ryanodine receptor. Nature 517: 44-49.

Zhao, M., P. Li, X. Li, L. Zhang, R.J. Winkfein and S.R.W. Chen (1999). Molecular identification of the ryanodine receptor pore-forming segment. J. Biol. Chem. 274: 25971-25974.

Zissimopoulos, S. and F.A. Lai. (2005). Interaction of FKBP12.6 with the cardiac ryanodine receptor C-terminal domain. J. Biol. Chem. 280: 5475-5485.

Zuo, Y.Y., H.H. Ma, W.J. Lu, X.L. Wang, S.W. Wu, R. Nauen, Y.D. Wu, and Y.H. Yang. (2020). Identification of the ryanodine receptor mutation I4743M and its contribution to diamide insecticide resistance in Spodoptera exigua (Lepidoptera: Noctuidae). Insect Sci 27: 791-800.

Examples:

TC#NameOrganismal TypeExample
1.A.3.1.1

Ryanodine receptor Ca2+ release channel, RyR2.  Causes Ca2+ release from the E.R. and consequent cardiac arrhythmia (Chelu and Wehrens, 2007). It associates with FKBP12.6, but phosphorylation by protein kinase A on serine-2030 causes dissociation (Jones et al., 2008). An interaction site for FKBP12.6 may be present at the RyR2 C terminus, proximal to the channel pore, a sterically appropriate location that would enable this protein to play a role in the modulation of this channel (Zissimopoulos and Lai 2005). Enhanced binding of calmodulin corrects arrhythmogenic channel disorder in myocytes (Fukuda et al. 2014).  RyR2s can open spontaneously, giving rise to spatially-confined Ca2+ release events known as "sparks." They are organized in a lattice to form clusters in the junctional sarcoplasmic reticulum membrane. The spatial arrangement of RyR2s within clusters strongly influences the frequency of Ca2+ sparks (Walker et al. 2015).  Structures of RyR2 from porcine heart in both the open and closed states at near atomic resolutions have been determined using single-particle electron cryomicroscopy (Peng et al. 2016). Structural comparisons revealed breathing motions of the overall cytoplasmic region resulting from the interdomain movements of amino-terminal domains (NTDs), Helical domains, and Handle domains, whereas little intradomain shifts are observed in these armadillo repeat-containing domains. Outward rotations of the central domains, which integrate the conformational changes of the cytoplasmic region, lead to the dilation of the cytoplasmic gate through coupled motions. These observations provide insight into the gating mechanism of RyRs (Peng et al. 2016). RyR2 is subject ot regulation by cytoplasmic Zn2+ (>1nM), and this regulation plays a key role in diastolic SR Ca2+ leakage in cardiac muscle (Reilly-O'Donnell et al. 2017). Ryanodine receptor-mediated SR Ca2+ efflux is apparently balanced by concomitant counterion currents across the SR membrane (Sanchez et al. 2018). Electrical polarity-dependent gating and a unique subconductance of RyR2 is induced by S-adenosyl methionine via the ATP binding site. Thus, SAM may alter the conformation of the RyR2 ion conduction pathway (Kampfer and Balog 2021). The brief opening mode of the mitochondrial permeability transition pore (mPTP) serves as a calcium (Ca2+) release valve to prevent mitochondrial Ca2+ (mCa2+) overload. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmic syndrome due to mutations in the Ca2+ release channel complex of ryanodine receptor 2 (RyR2). Genetic inhibition of mPTP exacerbates RyR2 dysfunction in CPVT by increasing activation of the CaMKII pathway and subsequent hyperphosphorylation of RyR2 (Deb et al. 2023). Protamine reversibly modulates the calcium release channel/ryanodine receptor 2 (RyR2) and voltage-dependent cardiac RyR2 (Yamada et al. 2023). Calcium release deficiency syndrome (CRDS) is a form of inherited arrhythmia caused by damaging loss-of-function variants in the cardiac ryanodine receptor (RyR2) (Kallas et al. 2023). Cardiomyocyte ryanodine receptor 2 clusters expand and coalesce after application of isoproterenol. Thus, isoproterenol induces rapid, significant, changes in the molecular architecture of excitation-contraction coupling (Scriven et al. 2023).  Distinct patterns and length scales of RyR and IP3R1 co-clustering at contact sites between the ER and the surface plasmalemma that encode the positions and the quantity of Ca2+ released at each Ca2+ spark (Hurley et al. 2023).  The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic (ER)/sarcoplasmic reticulum (SR) that plays a central role in the excitation-contraction coupling in the heart. Hyperactivity of RyR2 has been linked to ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia and heart failure, where spontaneous Ca2+ release via hyperactivated RyR2 depolarizes diastolic membrane potential to induce triggered activity. In such cases, drugs that suppress RyR2 activity are expected to prevent the arrhythmias. Such inhibitors have been identified (Takenaka et al. 2023).  VPS13A disease is associated with histopathological findings implicating abnormal lipid accumulation (Ditzel et al. 2023). Alarin (Claritin; Loratadine) regulates RyR2 and SERCA2 to improve cardiac function in heart failure with preserved ejection fraction (Li et al. 2024).

Animals

Cardiac muscle RyR-CaC of Homo sapiens

 
1.A.3.1.10

Ryanodine receptor, RyR, of 5139 aas and 6 TMSs. Sensitive to the diamide insecticides, chlorantraniliprole and flubendiamide. It has the conserved C-terminal domain with the consensus calcium-biding EF-hands (calcium-binding motif), the six transmembrane domains, as well as mannosyltransferase, IP3R and RyR (pfam02815) (MIR) domains (Wu et al. 2018). Probably transports monovalent cations and Ca2+.

RyR of Sesamia inferens (pink stem borer)

 
1.A.3.1.11

The ryanodine receptor of 5140 aas and 6 C-terminal TMSs. It is the targets of diamide insecticides. The mutation I4743M contributes to diamide insecticide resistance (Zuo et al. 2020). The diamide binding site on the Lepidopteran Ryanodine Receptor has been examined (Richardson et al. 2021).

RyR of Spodoptera exigua (beet armyworm) (Noctua fulgens)

 
1.A.3.1.2

The Ryanodine receptor Ca2+/K+ release tetrameric channel, RyR1, present in skeletal muscle, is 5038 aas long. Mutants are linked to core myopathies such as Central Core Disease, Malignant Hyperthermia and Multiple Minicore Disease) (Xu et al., 2008). RyR1 interacts with CLIC2 to modulate its channel activity (Meng et al., 2009).  A model pf RyR1 has been constructed encompassing the six transmembrane helices to calculate the RyR1 pore region conductance, to analyze its structural stability, and to hypothesize the mechanism of the Ile4897 CCD-associated mutation. The calculated conductance of the wild-type RyR1 suggests that the pore structure can sustain ion currents measured in single-channel experiments. Shirvanyants et al. 2014 observed a stable pore structure with multiple cations occupying the selectivity filter and cytosolic vestibule, but not the inner chamber. Stability of the selectivity filter depends on interactions between the I4897 residue and several hydrophobic residues of the neighboring subunit. Loss of these interactions in the case of the polar substitution, I4897T, results in destabilization of the selectivity filter, a possible cause of the CCD-specific reduced Ca2+ conductance.  A 4.8 Å structure of the rabbit orthologue in the closed state of this 2.3 MDa tetramer (3757 aas/protomer) reveals the pore, the VIC superfamily fold and a potential mechanism of Ca2+ gating (Zalk et al. 2015).  A cryo-electron microscopy analysis revealed the structure at 6.1 Å resolution (Efremov et al. 2015). The transmembrane domain represents a chimaera of voltage-gated sodium and pH-activated ion channels. They identified the calcium-binding EF-hand domain and showed that it functions as a conformational switch, allosterically gating the channel.  Malignant hyperthermia-associated RyR1 mutations in the S2-S3 loop confer RyR2-type Ca2+- and Mg2+-dependent channel regulation (Gomez et al. 2016).  Structural analyses have elucidated a novel channel-gating mechanism and a novel ion selectivity mechanism for RyR1 (Wei et al. 2016).  Samsó 2016 reviewed structural determinations of RyR by cryoEM and  analyzed the first near-atomic structures, revealing a complex orchestration of domains controlling channel function.  The structural basis for gating and activation have been determined (des Georges et al. 2016). Junctin and triadin bind to different sites on RyR1; triadin plays an important role in ensuring rapid Ca2+ release during excitation-contraction coupling in skeletal muscle.  RyR1 structure/functioin has been reviewed (Zalk and Marks 2017). Possibly, luminal Ca2+ activates RyR1 by accessing a cytosolic Ca2+ binding site in the open channel as the Ca2+ ions pass through the pore (Xu et al. 2017). The 3-d structures of the native protein in membranes has been determined (Chen and Kudryashev 2020) (see family description). The most common cause of nondystrophic congenital myopathies is mutations in RYR1 (Sorrentino 2022). Targeting ryanodine receptor type 2 can mitigate chemotherapy-induced neurocognitive impairments in mice (Liu et al. 2023).

Animals

RyR1 of Homo sapiens (P21817)

 
1.A.3.1.3

The Ryanodine Receptor homologue, RyRi (5,101 aas; 77% identical to the A gambiae RyR) of the aphid, Myzus persicae, is the tartet of diamide insecticides and is made without alternative splicing (Troczka et al. 2015). The almost identical well characterized orthologue from the oriential fruit fly, Bactrocera dorsalis also has its 6 TMSs C-terminal (Yuan et al. 2014).

Animals (Insects)

RyRi of Anopheles gambiae (Q7PMK5)

 
1.A.3.1.4

Ryanodine receptor (RyR) of 5107 aas.  Flubendiamine, a RyR-activating insecticide, induced Ca2+ release in hemocytes (Kato et al. 2009; Wu et al. 2013).

Animals (Insects)

RyR of Pieris rapae (white cabbage butterfly)

 
1.A.3.1.5

Ryanodine receptor (RyR) of 5127 aas and 6 TMSs. Intracellular calcium channel that is required for proper muscle function during embryonic development and may be essential for excitation-contraction coupling in larval body wall muscles. Mediates general anaesthesia by halothane (Gao et al. 2013) and confers sensitivity to diamide insecticides (Tao et al. 2013).

RyR of Drosophila melanogaster (Fruit fly)

 
1.A.3.1.6

Ryanodine-sensitive calcium release channel receptor, RyR of 5071 aas and 6 putative TMSs.  The tissue lecalization has been described (Hamada et al. 2002).  Required for neuronal regeneration (Sun et al. 2014).

RyR of Caenorhabditis elegans

 
1.A.3.1.7

Aphid ryanodine receptor RyR) of 5105 aas and 6 TMSs, a target of insecticides.  The sequence of the Acyrthosiphon pisum (Pea aphid) is provided below, but the Toxoptera citricida (98% identiy; Brown citrus aphid; Aphis citricidus) RyR was studied (Wang et al. 2015).

Aphid RyR of Acyrthosiphon pisum (Pea aphid)

 
1.A.3.1.8

Ryanodine receptor, DcRyR shows high sequence identity to RyRs from other insects (76%-95%) and shares many features of insect and vertebrate RyRs, including a MIR domain, two RIH domains, three SPRY domains, four copies of RyR repeat domain, an RIH-associated domain at the N-terminus, two consensus calcium-binding EF-hands and six TMSs at the C-terminus (Yuan et al. 2017). The expression of DcRyR mRNA was the highest in the nymphs and lowest in eggs; it has three alternative splice sites, and the splice variants showed body part-specific expression, being under developmentally regulation (Yuan et al. 2017).

RyR of Dialeurodes citri (Citrus whitefly) (Aleurodes citri)

 
1.A.3.1.9

Ryanodine-sensitive Ca2+ release channel RyR1 of 5117 aas and 6 TMSs.  Diamide insecticides, such as flubendiamide and chlorantraniliprole, selectively activate insect ryanodine receptors of Lepidoptera and Coleoptera pests (Samurkas et al. 2020). They are particularly active against lepidopteran pests of cruciferous vegetable crops, including the diamondback moth, Plutella xylostella. Resistance results from mutation(s) in the ryanodine receptors' transmembrane domain at the C-termini of these proteins (Troczka et al. 2017). Other diamide insecticides, including phthalic and anthranilic diamides, target insect ryanodine receptors (RyRs) and cause misregulation of calcium signaling in insect muscles and neurons. Homology modeling and docking studies with the diamondback moth ryanodine receptor revealed the mechanisms for channel activation, insecticide binding, and resistance (Lin et al. 2019).

RyR1 of Plutella xylostella (Diamondback moth) (Plutella maculipennis)

 
Examples:

TC#NameOrganismal TypeExample
1.A.3.2.1

Inositol 1,4,5-trisphosphate receptor-2 with 2701 aas and 6 TMSs.  Mediates release of intracellular calcium which is regulated by cAMP both dependently and independently of PKA and plays a critical role in cell cycle regulation and cell proliferation.  High level expression in humans is an indication of cytogenetically normal acute myeloid leukemia (CN-AML) (Shi et al. 2015).

.  

Animals

Brain IP3-CaC of Rattus norvegicus

 
1.A.3.2.10

Calcium release channel III, CRCIII1a of 2598 aas.  Associated with recycling vesicles engaged in phagosome formation (Ladenburger and Plattner 2011).

Alveolata (Ciliates)

CRCIII1a of Paramecium tetraurelia

 
1.A.3.2.11

Calcium release channel IV3b, CRCIV3b, of 3127 aas.  Display structural and functional properties of ryanodine receptors (Ladenburger et al. 2009).  Localized to the alveolar sacs of the cortical subplasmalemmal Ca2+-stores (Plattner et al. 2012).  Involved in exocytosis in response to ryanodine receptor agonists (Docampo et al. 2013).

Alveolata (Ciliates)

CRCIV3b of Paramecium tetraurelia

 
1.A.3.2.12

Calcium release channel V-4b, CRCV4b of 2589 aas.  Occurs in parasomal (alveolar) sacs (clathrin coated pits) (Docampo et al. 2013).

Alveolata (Ciliates)

CRCV4b of Paramecium tetraurelia

 
1.A.3.2.13

Calcium release channel VI-2b, CRCVI2b.  Localized to the contractile vacuole (Docampo et al. 2013).

Alveolata (Ciliates)

CRCVI2b of Paramecium tetraurelia

 
1.A.3.2.14

Endoplasmic reticular inositol triphosphate receptor, IP3R of 3099 aas (Docampo et al. 2013).

Euglenozoa (Protozoa)

IP3R of Trypanosoma brucei

 
1.A.3.2.16

Inositol triphosphate receptor, IP3R, also called Itr-1, Dec-4 and Ife-1, of 2892 aas and 6 TMSs (Baylis and Vázquez-Manrique 2012).  Receptor for inositol 1,4,5-trisphosphate, a second messenger that regulates intracellular calcium homeostasis. Binds in vitro to both 1,4,5-InsP3 and 2,4,5-InsP3 with high affinity and does not discriminate between the phosphate at the 1 or 2 position. Can also bind inositol 1,3,4,5-tetrakisphosphate (1,3,4,5-InsP4) and inositol 4,5-bisphosphate (4,5-InsP2), but with lower affinity. Acts as a timekeeper/rhythm generator via calcium signaling, affecting the defecation cycle and pharyngeal pumping (Dal Santo et al. 1999). Affects normal hermaphrodite and male fertility as a participant in intracellular signaling by acting downstream of let-23/lin-3 which regulates ovulation, spermathecal valve dilation and male mating behavior (Walker et al. 2002Gower et al. 2005). Important for early embryonic development; controls epidermal cell migration and may also regulate filopodial protrusive activity during epithelial morphogenesis (Thomas-Virnig et al. 2004; ). Component of inositol trisphosphate (IP3)-mediated downstream signaling pathways that controls amphid sensory neuronal (ASH)-mediated response to nose touch and benzaldehyde (Walker et al. 2009).

IP3 receptor of Caenorhabditis elegans

 
1.A.3.2.17

IP3R of 3140 aas, RyR1 (Wheeler and Brownlee 2008).

IP3R of Chlamydomonas reinhardtii

 
1.A.3.2.2

The Inositol 1,4,5- triphosphate (InsP3)-like receptor (2838aas). Receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium. May be involved in visual and olfactory transduction as well as myoblast proliferation.   Loss in adult neurons results in obesity in adult flies (Subramanian et al. 2013).

Animals

InsP3l receptor Drosophila melanogaster (P29993)

 
1.A.3.2.3The cation channel family protein, IsnP3-like protein (2872aas)

Ciliates

InsP3-like protein of Tetrahymena themophila (Q23K98)

 
1.A.3.2.4

The Inositol 1,4,5- triphosphate (InsP3)-like receptor (3036aas) (Ladenburger et al. 2009; Docampo et al. 2013).

Ciliates

InsP3l receptor of Paramecium tetraaurelia (A0CX44)

 
1.A.3.2.5

The rat inositol trisphosphate receptor (IP3R; IP(3)R1) is dispensable for rotavirus-induced Ca2+ signaling and replication but critical for paracrine Ca2+ signals that prime uninfected cells for rapid virus spread (Subedi et al., 2012; Perry et al. 2023).  The human orthologue, IP3R3, is regulated at the ER-mitochondrion interface by BCL-XL (TC# 1.A.21.1.6) (Williams et al. 2016). Genetic polymorphisms of Ca2+ transport proteins and molecular chaperones in mitochondria-associated endoplasmic reticulum membranes and non-alcoholic fatty liver disease (NAFA5) have been identified. The variant genotypes of Ca2+ transport-associated genes HSPA5 (rs12009 and rs430397) and ITPR2 (rs11048570) probably contribute to the reduction of the NAFLD risk in the Chinese Han population (Tang et al. 2022).  Host IP3R channels are dispensable for rotavirus Ca2+ signaling but critical for intercellular Ca2+ waves that prime uninfected cells for rapid virus spread (Perry et al. 2024).  

Animals

IP(3)R1 of Rattus norvegicus (Q63269)

 
1.A.3.2.6

Inositol 1,4,5-trisphosphate receptor type 1 (IP3 receptor isoform 1; ITPR1; IP3R 1; InsP3R1; Itpr1) (Type 1 inositol 1,4,5-trisphosphate receptor) (Type 1 InsP3 receptor) of 2758 aas and 6 TMSs near the C-terminus. An intronic variant in ITPR1 causes Gillespie syndrome, characterized by bilateral symmetric partial aplasia of the iris presenting as a fixed and large pupil, cerebellar hypoplasia with ataxia, congenital hypotonia, and varying levels of intellectual disability (Keehan et al. 2021). The cryoEM structure has been determined (Baker et al. 2021). Binding of the erlin1/2 complex (TC# 8.A.195) to the third intralumenal loop of IP3R1 triggers its ubiquitin-proteasomal degradation (Gao et al. 2022). IP3R channels participate in the reticular Ca2+ leak towards mitochondria (Gouriou et al. 2023).  It is a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia (Tolonen et al. 2023).  Aberrant Ca2+ signaling is a key link between human pathogenic PSEN1 (Presenilin-1 variants (PSEN1 p.A246E, p.L286V, and p.M146L)) and cell-intrinsic hyperactivity prior to deposition of abnormal Aß (Hori et al. 2024).

Animals

ITPR1 of Homo sapiens

 
1.A.3.2.7

Contractile vacuole complex calcium release channel (CRC)II; IP3Rn (Ladenburger et al. 2006).  Functions in osmoregulation by promoting expulsion of water and some ions including Ca2+.  Also functions in calcium homeostasis (Ladenburger et al. 2006; Docampo et al. 2013).

Ciliates (Alveolata)

IP3Rn or CRCII of Paramecium trtraurelia

 
1.A.3.2.8

Putative IP3R calcium-release channel VI-3 of 2021 aas (Docampo et al., 2013).

Ciliates

Calcium-release channel VI-3 of Paramecium tetraurelia

 
1.A.3.2.9

CRCI-1a; IP3R.  Functions similarly to TC# 1.A.3.2.7 (Docampo et al. 2013).  Cortical Ca2+ stores (alveolar sacs) are activated during stimulated trichocyst exocytosis, mediating store-operated Ca2+ entry (SOCE). Ca2+ release channels (CRCs) localise to alveoli and are Ryanodine receptor-like proteins (RyR-LPs) as well as inositol 1,4,5-trisphosphate receptors (IP3Rs), members of the CRC family with 6 subfamilies (Plattner 2014).

Ciliates (Alveolata)

CRCI-1a of Paramecium tetraurelia