Summary: RyR domain
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Ryanodine receptor Edit Wikipedia article
Ryanodine receptors (RyRs) form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons. It is the major cellular mediator of calcium-induced calcium release (CICR) in animal cells.
There are multiple isoforms of ryanodine receptors:
- RyR1 is primarily expressed in skeletal muscle
- RyR2 in myocardium (heart muscle)
- A third form, RyR3, is expressed more widely, but especially in the brain.
- There is also a fourth form found only in fish.
Ryanodine receptors mediate the release of calcium ions from the sarcoplasmic reticulum, an essential step in muscle contraction. In skeletal muscle, it is thought that activation occurs via a physical coupling to the dihydropyridine receptor, whereas, in cardiac muscle, the primary mechanism is calcium-induced calcium release from the sarcoplasmic reticulum.
It has been shown that calcium release from a number of ryanodine receptors in a ryanodine receptor cluster results in a spatiotemporally restricted rise in cytosolic calcium that can be visualised as a calcium spark.
Ryanodine receptors are similar to the inositol trisphosphate (IP3) receptor, and stimulated to transport Ca2+ into the cytosol by recognizing Ca2+ on its cytosolic side, thus establishing a positive feedback mechanism; a small amount of Ca2+ in the cytosol near the receptor will cause it to release even more Ca2+ (calcium-induced calcium release/CICR).
The localized and time-limited activity of Ca2+ in the cytosol is also called a Ca2+ wave. The building of the wave is done by
- the feedback mechanism of the ryanodine receptor
- the activation of phospholipase C by GPCR or TRK, which leads to the production of inositol trisphosphate, which in turn activates the InsP3 receptor.
 Associated proteins
Many other proteins with various functions are associated with RyR . For instance in RyR2 from luminal side it is calsequestrin which forms quaternary structure of RyR along with junctin and triadin. Calsequestrin has multiple Ca2+ binding sites and binds Ca2+ ions with very low affinty so they can be easily released.
Ryanodine receptors are usually found in clusters of 3 or 4 (i.e. they are associated with each other)and it was observed that they are to some extent able to open and close simultaneously. This happens more often in physiological conditions and is less observed in vitro.
- Agonist: 4-chloro-m-cresol and suramin are direct agonists, i.e., direct activators.
- Xanthines like caffeine and pentifylline activate it by potentiating sensitivity to native ligand Ca.
- Physiological agonist: Cyclic ADP-ribose can act as a physiological gating agent. It has been suggested that it may act by making FKBP12.6 (12.6 kilodalton FK506 binding protein, as opposed to 12 kDa FKBP12 which binds to RyR1) which normally bind (and blocks) RyR2 channel tetramer in an average stoichiometry of 3.6, to fall off RyR2 (which is the predominant RyR in pancreatic beta cells, cardiomyocytes and smooth muscles).
A variety of other molecules may interact with and regulate Ryanodine receptor. For example: Dimerized Homer physical tether linking inositol trisphosphate receptors (IP3R) and ryanodine receptors on the intracellular calcium stores with cell surface group 1 metabotropic Glutamate Receptors and the alpha 1D adrenergic receptor
The plant alkaloid ryanodine, for which this receptor was named, has become an invaluable investigative tool. It can block the phasic release of calcium, but at low doses may not block the tonic cumulative calcium release. The binding of ryanodine to RyRs is use-dependent, that is the channels have to be in the activated state. At low (<10 MicroMolar, works even at nanomolar) concentrations, ryanodine binding locks the RyRs into a long-lived subconductance (half-open) state and eventually depletes the store, while higher (~100 MicroMolar) concentrations irreversibly inhibit channel-opening.
RyRs are activated by millimolar caffeine concentrations. High (greater than 5 mmol/L) caffeine concentrations cause a pronounced increase (from micromolar to picomolar) in the sensitivity of RyRs to Ca2+ in the presence of caffeine, such that basal Ca2+ concentrations become activatory. At low millimolar caffeine concentrations, the receptor opens in a quantal way, but has complicated behavior in terms of repeated use of caffeine or dependence on cytosolic or luminal calcium concentrations.
 Role in disease
RyR1 mutations are associated with malignant hyperthermia and central core disease. RyR2 mutations play a role in stress-induced polymorphic ventricular tachycardia (a form of cardiac arrhythmia) and ARVD. It has also been shown that levels of type RyR3 are greatly increased in PC12 cells overexpressing mutant human Presenilin 1, and in brain tissue in knockin mice that express mutant Presenilin 1 at normal levels, and thus may play a role in the pathogenesis of neurodegenerative diseases, like Alzheimer's disease.
 Human proteins containing this domain
 See also
- Ryanoid, a class of insecticide that act through ryanodine receptors
- Zucchi R, Ronca-Testoni S (March 1997). "The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor: modulation by endogenous effectors, drugs and disease states". Pharmacol. Rev. 49 (1): 1â51. PMID 9085308.
- Fabiato A (1983). "Calcium-induced calcium release of calcium from the cardiac sarcoplasmic reticulum". Am J Physiol 245 (1): C1âC14. PMID 6346892.
- Cheng H, Lederer WJ, Cannell MB (1993). "Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle". Science 262 (5134): 740â744. doi:10.1126/science.8235594. PMID 8235594.
- Vites A, Pappano A (1994). "Distinct modes of inhibition by ruthenium red and ryanodine of calcium-induced calcium release in avian atrium". J Pharmacol Exp Ther 268 (3): 1476â84. PMID 7511166.
- Xu L, Tripathy A, Pasek D, Meissner G (1998). "Potential for pharmacology of ryanodine receptor/calcium release channels". Ann N Y Acad Sci 853: 130â48. doi:10.1111/j.1749-6632.1998.tb08262.x. PMID 10603942.
- Wang Y, Zheng Y, Mei Q, Wang Q, Collier M, Fleischer S, Xin H, Kotlikoff M (2004). "FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells". Am J Physiol Cell Physiol 286 (3): C538â46. doi:10.1152/ajpcell.00106.2003. PMID 14592808.
- Tu J, Xiao B, Yuan J, Lanahan A, Leoffert K, Li M, Linden D, Worley P (1998). "Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors". Neuron 21 (4): 717â26. doi:10.1016/S0896-6273(00)80589-9. PMID 9808459.
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RyR domain Provide feedback
This domain is called RyR for Ryanodine receptor . The domain is found in four copies in the ryanodine receptor. The function of this domain is unknown.
External database links
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Number in seed:||38|
|Number in full:||1192|
|Average length of the domain:||92.00 aa|
|Average identity of full alignment:||37 %|
|Average coverage of the sequence by the domain:||8.15 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||11|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
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There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
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Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the RyR domain has been found. There are 22 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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