Cellular functions of immunophilins

1996 ◽  
Vol 76 (3) ◽  
pp. 631-649 ◽  
Author(s):  
A. R. Marks
Keyword(s):  
Calcium Release ◽  
Ryanodine Receptors ◽  
Cellular Functions ◽  
Prolyl Isomerase ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Isomerase Activity ◽  
Channel Function ◽  
Enzymatic Function ◽  
Peptidyl Prolyl Isomerases

Immunophilins are members of a highly conserved family of proteins all of which are cis-trans peptidyl-prolyl isomerases. The prototypic members of the immunophilin family, cyclophilin A and FKPB12, were discovered on the basis of their ability to bind and mediate the immunosuppressive effects of the drugs cyclosporin, FK506, and rapamycin. However, the prolyl isomerase activity of these proteins is not involved in any of the immunosuppressive effects. Indeed, despite the fact that all members of the family are prolyl isomerases, the cellular role of this enzymatic function has not been clearly defined. In many cases, immunophilins are widely expressed and are present at high levels in some tissues. Moreover, while the number of proteins that belong to the immunophilin family continues to grow, the natural cellular functions of all but a few remain obscure. An example where immunophilins do appear to have a defined cellular role, in the absence of immunosuppressive ligands, is the modulation of intracellular calcium release channel function by FKBP12 and FKBP12.6. In this case, FKBPs are integral parts of three types of calcium release channel complexes, skeletal and cardiac ryanodine receptors and the inositol 1,4,5-trisphosphate receptor. In each case, FKBPs modulate channel function possibly by enhancing the cooperativity between subunits.

scholarly journals Unravelling calcium-release channel gating: clues from a hot disease

2004 ◽  
Vol 380 (1) ◽  
pp. e1-e3 ◽  
Author(s):  
Tommie V. McCARTHY ◽  
John J. MACKRILL
Keyword(s):  
Calcium Release ◽  
Distinct Point ◽  
Ryanodine Receptors ◽  
Point Mutations ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Present Evidence ◽  
Gating Mechanism ◽  
Biochemical Journal ◽  
Interdomain Interactions

Ryanodine receptors (RyRs) are a family of intracellular channels that mediate Ca2+ release from the endoplasmic and sarcoplasmic reticulum. More than 50 distinct point mutations in one member of this family, RyR1, cause malignant hyperthermia, a potentially lethal pharmacogenetic disorder of skeletal muscle. These mutations are not randomly distributed throughout the primary structure of RyR1, but are grouped in three discrete clusters. In this issue of the Biochemical Journal, Kobayashi et al. present evidence that interdomain interactions between two of these mutation-enriched regions play a key role in the gating mechanism of RyR1.

The Ryanodine Receptor/Calcium Release Channel and its Interaction Partners

1998 ◽  
Vol 4 (S2) ◽  
pp. 968-969
Author(s):  
Terry Wagenknecht ◽  
Montserrat Samso
Keyword(s):  
Calcium Release ◽  
Striated Muscle ◽  
Ryanodine Receptors ◽  
Three Dimensional ◽  
Structural Complexity ◽  
Body Representation ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Fk506 Binding Protein ◽  
Dimensional Reconstruction

Ryanodine receptors (RyRs) function as the major intracellular calcium release channels in striated muscle, where they also play a central role in excitation-contraction (e-c) coupling, the signal transduction process by which neuron-induced depolarization of the muscle plasma membrane leads to release of Ca from the sarcoplasmic reticulum. Structurally, RyRs are the largest ion channels known, being composed of 4 identical large subunits (565 kDa). In situ, RyRs interact with numerous proteins that are essential for e-c coupling or regulation thereof. Some of these ligands include calmodulin, a 12-kDa FK506-binding protein (FKBP, an immunophi1 in), calsequestrin, triadin, and the dihydropyridine receptor (DHPR).Detergent-solubilized, purified RyRs appear to retain their native structure as assessed by electron cryo-microscopy, and are amenable to three-dimensional reconstruction by single-particle image processing techniques. In Fig. 1, a solid-body representation of the reconstructed skeletal muscle RyR shows the structural complexity that is revealed at moderate resolutions (3-4 nm).

scholarly journals Type 3 and Type 1 Ryanodine Receptors Are Localized in Triads of the Same Mammalian Skeletal Muscle Fibers

1999 ◽  
Vol 146 (3) ◽  
pp. 621-630 ◽  
Author(s):  
Bernhard E. Flucher ◽  
Antonio Conti ◽  
Hiroshi Takeshima ◽  
Vincenzo Sorrentino
Keyword(s):  
Skeletal Muscle ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Physiological Role ◽  
Fiber Types ◽  
Mammalian Skeletal Muscle ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Accessory Function ◽  
Type 3

The type 3 ryanodine receptor (RyR3) is a ubiquitous calcium release channel that has recently been found in mammalian skeletal muscles. However, in contrast to the skeletal muscle isoform (RyR1), neither the subcellular distribution nor the physiological role of RyR3 are known. Here, we used isoform-specific antibodies to localize RyR3 in muscles of normal and RyR knockout mice. In normal hind limb and diaphragm muscles of young mice, RyR3 was expressed in all fibers where it was codistributed with RyR1 and with the skeletal muscle dihydropyridine receptor. This distribution pattern indicates that RyR3 is localized in the triadic junctions between the transverse tubules and the sarcoplasmic reticulum. During development, RyR3 expression declined rapidly in some fibers whereas other fibers maintained expression of RyR3 into adulthood. Comparing the distribution of RyR3-containing fibers with that of known fiber types did not show a direct correlation. Targeted deletion of the RyR1 or RyR3 gene resulted in the expected loss of the targeted isoform, but had no adverse effects on the expression and localization of the respective other RyR isoform. The localization of RyR3 in skeletal muscle triads, together with RyR1, is consistent with an accessory function of RyR3 in skeletal muscle excitation–contraction coupling.

Amplifying long transcripts of ryanodine receptors of five agricultural pests by transcriptome analysis and gap filling

Genome ◽  
2013 ◽  
Vol 56 (11) ◽  
pp. 651-658 ◽  
Author(s):  
Yonglei Liu ◽  
Muhammad Faisal Shahzad ◽  
Lan Zhang ◽  
Fei Li ◽  
Kejian Lin
Keyword(s):  
Calcium Release ◽  
Ryanodine Receptors ◽  
Resistance Mechanism ◽  
Full Length ◽  
Cnaphalocrocis Medinalis ◽  
Agricultural Pests ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Rapid Amplification ◽  
Molecular Manipulation

Ryanodine receptor (RyR) is an intracellular calcium release channel that plays a key role in excitation contraction coupling. Insect RyR is the target of diamide insecticides. Better understanding of insect RyR is necessary for studying the molecular mode of action and potential resistance mechanism of diamide insecticides. However, molecular manipulation of the full RyR gene is difficult because of its length (approximately 15 kb). At present, RyR genes have been reported only in a limited number of insects. Here, we developed an efficient strategy to amplify full-length transcripts of insect RyR genes. First, we searched the transcriptomes of five insects, Bemisia tabaci, Cnaphalocrocis medinalis, Chilo suppressalis, Laodelphgax striatellus, and Plutella xylostella, yielding 85 RyR contigs in total. Second, the relative positions of these contigs in RyR transcripts were determined by aligning them with 12 well-annotated RyRs. Third, we designed primers to fill gaps between contigs and used rapid amplification of cDNA ends (RACE) to amplify both 5′- and 3′-ends. Last, we assembled all fragments into long transcripts. As a result, full-length transcripts of three insects, C. suppressalis, L. striatellus, and P. xylostella, were obtained. The RyR transcript of B. tabaci was near full length, containing an intact ORF. Northern blot analysis indicated that RyR genes were expressed in all five insects. Sequence analyses showed that the amplified insect segments contained typical RyRs characteristics, such as EF-hand, motif GVRAGGGIGD, and six transmembrane domains. Seven lepidopteran-specific amino acid residues were found to be located in the C-terminal region of RyR proteins, which might be associated with the specificity of RyRs to diamide insecticides.

scholarly journals β-Blockers Restore Calcium Release Channel Function and Improve Cardiac Muscle Performance in Human Heart Failure

Circulation ◽  
2003 ◽  
Vol 107 (19) ◽  
pp. 2459-2466 ◽  
Author(s):  
Steven Reiken ◽  
Xander H.T. Wehrens ◽  
John A. Vest ◽  
Alessandro Barbone ◽  
Stefan Klotz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Muscle ◽  
Human Heart ◽  
Calcium Release ◽  
Muscle Performance ◽  
Calcium Release Channel ◽  
Human Heart Failure ◽  
Release Channel ◽  
Channel Function ◽  
Β Blockers

Hypochlorous acid modifies calcium release channel function from skeletal muscle sarcoplasmic reticulum

2003 ◽  
Vol 94 (4) ◽  
pp. 1387-1394 ◽  
Author(s):  
Terence G. Favero ◽  
Jason Webb ◽  
Maria Papiez ◽  
Erin Fisher ◽  
Robert J. Trippichio ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Lipid Membrane ◽  
Hypochlorous Acid ◽  
Release Mechanism ◽  
Dependent Manner ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Binding Behavior ◽  
Channel Function

We have previously demonstrated that H2O2 at millimolar concentrations induces Ca2+ release from actively loaded sarcoplasmic reticulum (SR) vesicles and induces biphasic [3H]ryanodine binding behavior. Considering that hypochlorous acid (HOCl) is a related free radical and has been demonstrated to be a more effective oxidant of proteins, we evaluated the effects of HOCl on sarcoplasmic reticulum Ca2+-channel release mechanism. In a concentration-dependent manner, HOCl activates the SR Ca2+release channel and induces rapid release of Ca from actively loaded vesicles. HOCl-induced Ca2+ release is inhibited in the presence of millimolar concentrations of DMSO. High-affinity [3H]ryanodine binding is also enhanced at concentrations from 10 to 100 μM. At HOCl concentrations of >100 μM, equilibrium binding is inhibited. HOCl stimulation of binding is inhibited by the addition of dithiothreitol. The direct interaction between HOCl and the Ca2+ release mechanism was further demonstrated in single-channel reconstitution experiments. HOCl, at 20 μM, activated the Ca2+ release channel after fusion of a SR vesicle to a bilayer lipid membrane. At 40 μM, Ca2+-channel activity was inhibited. Pretreatment of SR vesicles with HOCl inhibited the fluorescence development of a fluorogenic probe specific to thiol groups critical to channel function. These results suggest that HOCl at micromolar concentrations can modify SR Ca2+ handling.

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