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Ryanodine receptors
E Michelle Capes, Randall Loaiza, Héctor H Valdivia
Skeletal Muscle , 2011, DOI: 10.1186/2044-5040-1-18
Abstract: In striated and smooth muscle cells, fluctuations in the intracellular levels of Ca2+ ions greatly determine the magnitude and duration of contractile force. In cardiac and skeletal muscle, depolarization of the external membrane and its invaginations, the T-tubules, elicits swift and massive Ca2+ release from the sarcoplasmic reticulum (SR), which in turn causes 'flooding' of the contractile myofilaments with Ca2+ and induction of contraction. This exquisitely coordinated series of events, in which an electrical stimulus (depolarization) is converted into a mechanical contraction, is collectively termed 'excitation-contraction (EC) coupling', and it has as central players the voltage-dependent Ca2+ channels/dihydropyridine receptors (DHPRs) as the sarcolemmal voltage sensors, and the Ca2+ release channels/ryanodine receptors (RyRs) as the SR Ca2+ release conduits. The structural and functional communication between the voltage sensor and the RyR dictate the magnitude of Ca2+ release from the SR, and thus the force of contraction. In fact, genetic mutations in either of these two proteins, or alterations in the environment that promotes their functional coupling, are known to cause ventricular arrhythmias, hypercontractures and/or pathological remodeling of cellular structures. Excellent reviews on DHPRs have appeared recently [1,2]. In the current review, we focus on RyRs to discuss their most prominent structural and functional attributes, and to suggest mechanisms by which their dysfunction leads to disease.RyRs are not restricted to striated muscle. This class of intracellular Ca2+ release channels is also found in the endoplasmic reticulum of neurons, exocrine cells, smooth-muscle cells, epithelial cells, lymphocytes, sea-urchin eggs, and many others [3]. In all of these cells, RyRs play a central role in the regulation of the intracellular free Ca2+ concentration ([Ca2+]i), whose elevation triggers a cascade of events that culminates in, for example, neurotran
The structural biology of ryanodine receptors
Lynn Kimlicka,Filip Van Petegem
Science China Life Sciences , 2011, DOI: 10.1007/s11427-011-4198-2
Abstract: Ryanodine receptors are ion channels that allow for the release of Ca2+ from the endoplasmic or sarcoplasmic reticulum. They are expressed in many different cell types but are best known for their predominance in skeletal and cardiac myocytes, where they are directly involved in excitation-contraction coupling. With molecular weights exceeding 2 MDa, Ryanodine Receptors are the largest ion channels known to date and present major challenges for structural biology. Since their discovery in the 1980s, significant progress has been made in understanding their behaviour through multiple structural methods. Cryo-electron microscopy reconstructions of intact channels depict a mushroom-shaped structure with a large cytoplasmic region that presents many binding sites for regulatory molecules. This region undergoes significant motions during opening and closing of the channel, demonstrating that the Ryanodine Receptor is a bona fide allosteric protein. High-resolution structures through X-ray crystallography and NMR currently cover ~11% of the entire protein. The combination of high- and low-resolution methods allows us to build pseudo-atomic models. Here we present an overview of the electron microscopy, NMR, and crystallographic analyses of this membrane protein giant.
Phosphorylation of Ryanodine Receptors
Biological Research , 2004, DOI: 10.4067/S0716-97602004000400005
Abstract: both cardiac and skeletal muscle ryanodine receptors (ryrs) are parts of large complexes that include a number of kinases and phosphatases. these ryrs have several potential phosphorylation sites in their cytoplasmic domains, but the functional consequences of phosphorylation and the identity of the enzymes responsible have been subjects of considerable controversy. hyperphosphorylation of ser-2809 in ryr2 (cardiac isoform) and ser-2843 in ryr1 (skeletal isoform) has been suggested to cause the dissociation of the fk506-binding protein (fkbp) from ryrs, producing "leaky channels," but some laboratories find no relationship between phosphorylation and fkbp binding. also debated is the identity of the kinases that phosphorylate these serines: camp-dependent protein kinase (pka) versus calmodulin kinase ii (camkii). phosphorylation of other targets of these kinases could also alter calcium homeostasis. for example, pka also phosphorylates phospholamban (plb), altering the sarco-endoplasmic reticulum ca2+ atpase (serca) activity. this review summarizes the major findings and controversies associated with phosphorylation of ryrs.
Phosphorylation of Ryanodine Receptors  [cached]
Biological Research , 2004,
Abstract: Both cardiac and skeletal muscle ryanodine receptors (RyRs) are parts of large complexes that include a number of kinases and phosphatases. These RyRs have several potential phosphorylation sites in their cytoplasmic domains, but the functional consequences of phosphorylation and the identity of the enzymes responsible have been subjects of considerable controversy. Hyperphosphorylation of Ser-2809 in RyR2 (cardiac isoform) and Ser-2843 in RyR1 (skeletal isoform) has been suggested to cause the dissociation of the FK506-binding protein (FKBP) from RyRs, producing "leaky channels," but some laboratories find no relationship between phosphorylation and FKBP binding. Also debated is the identity of the kinases that phosphorylate these serines: cAMP-dependent protein kinase (PKA) versus calmodulin kinase II (CaMKII). Phosphorylation of other targets of these kinases could also alter calcium homeostasis. For example, PKA also phosphorylates phospholamban (PLB), altering the Sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) activity. This review summarizes the major findings and controversies associated with phosphorylation of RyRs.
Electrophysiology of Sodium Receptors in Taste Cells  [PDF]
Albertino Bigiani
Journal of Biomedical Science and Engineering (JBiSE) , 2016, DOI: 10.4236/jbise.2016.98032
Abstract: Sodium intake is important to maintain proper osmolarity and volume of extracellular fluid in vertebrates. The ability to find sources of sodium ions for managing electrolyte homeostasis relies on the activity of the taste system to sense salt. Several studies have been performed to understand the mechanisms underlying Na+ reception in taste cells, the peripheral detectors for food chemicals. It is now generally accepted that Na+ interacts with specific ion channels in taste cell membrane, called sodium receptors. As ion channels, these proteins mediate transmembrane ion fluxes (that is, electrical currents) during their operation. Thus, a lot of information on the functional properties of sodium receptors has been obtained by using electrophysiological techniques. Here, I review our current knowledge on the biophysical and physiological features of these receptors obtained by applying the patch-clamp recording techniques to single taste cells.
Mouse taste cells with G protein-coupled taste receptors lack voltage-gated calcium channels and SNAP-25
Tod R Clapp, Kathryn F Medler, Sami Damak, Robert F Margolskee, Sue C Kinnamon
BMC Biology , 2006, DOI: 10.1186/1741-7007-4-7
Abstract: Depolarization with high K+ resulted in an increase in intracellular Ca2+ in a small subset of non-GFP labeled cells of both transgenic mouse lines. In contrast, no depolarization-evoked Ca2+ responses were observed in GFP-expressing taste cells of either genotype, but GFP-labeled cells responded to the PLC activator m-3M3FBS, suggesting that these cells were viable. Whole cell recording indicated that the GFP-labeled cells of both genotypes had small voltage-dependent Na+ and K+ currents, but no evidence of Ca2+ currents. A subset of non-GFP labeled taste cells exhibited large voltage-dependent Na+ and K+ currents and a high threshold voltage-gated Ca2+ current. Immunocytochemistry indicated that SNAP-25 was expressed in a separate population of taste cells from those expressing T1R3 or TRPM5. These data indicate that G protein-coupled taste receptors and conventional synaptic signaling mechanisms are expressed in separate populations of taste cells.The taste receptor cells responsible for the transduction of bitter, sweet, and umami stimuli are unlikely to communicate with nerve fibers by using conventional chemical synapses.Taste buds, the transducing elements of gustatory sensation, contain a heterogeneous population of 50 to 100 elongate taste receptor cells, which extend from the basal lamina to the surface of the epithelium. Taste stimuli interact with receptors on the apical membrane, while the basolateral membranes of some taste cells associate with gustatory nerve fibers to transmit taste information to the brain.Several types of taste cells have been identified morphologically. Type I cells, also known as "dark" cells, generally comprise about half of the taste bud. These cells are not believed to have a receptive function, but to play a more glial-like role in the taste bud [1,2]. About 35% of the cells are Type II cells, which are also known as "light" cells due to the electron lucent nature of their cytoplasm. Type II cells express T1R and T2R taste re
Hedonic Taste in Drosophila Revealed by Olfactory Receptors Expressed in Taste Neurons  [PDF]
Makoto Hiroi, Teiichi Tanimura, Frédéric Marion-Poll
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002610
Abstract: Taste and olfaction are each tuned to a unique set of chemicals in the outside world, and their corresponding sensory spaces are mapped in different areas in the brain. This dichotomy matches categories of receptors detecting molecules either in the gaseous or in the liquid phase in terrestrial animals. However, in Drosophila olfactory and gustatory neurons express receptors which belong to the same family of 7-transmembrane domain proteins. Striking overlaps exist in their sequence structure and in their expression pattern, suggesting that there might be some functional commonalities between them. In this work, we tested the assumption that Drosophila olfactory receptor proteins are compatible with taste neurons by ectopically expressing an olfactory receptor (OR22a and OR83b) for which ligands are known. Using electrophysiological recordings, we show that the transformed taste neurons are excited by odor ligands as by their cognate tastants. The wiring of these neurons to the brain seems unchanged and no additional connections to the antennal lobe were detected. The odor ligands detected by the olfactory receptor acquire a new hedonic value, inducing appetitive or aversive behaviors depending on the categories of taste neurons in which they are expressed i.e. sugar- or bitter-sensing cells expressing either Gr5a or Gr66a receptors. Taste neurons expressing ectopic olfactory receptors can sense odors at close range either in the aerial phase or by contact, in a lipophilic phase. The responses of the transformed taste neurons to the odorant are similar to those obtained with tastants. The hedonic value attributed to tastants is directly linked to the taste neurons in which their receptors are expressed.
Expression of GABAergic Receptors in Mouse Taste Receptor Cells  [PDF]
Margaret R. Starostik,Michelle R. Rebello,Kellie A. Cotter,Akos Kulik,Kathryn F. Medler
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013639
Abstract: Multiple excitatory neurotransmitters have been identified in the mammalian taste transduction, with few studies focused on inhibitory neurotransmitters. Since the synthetic enzyme glutamate decarboxylase (GAD) for gamma-aminobutyric acid (GABA) is expressed in a subset of mouse taste cells, we hypothesized that other components of the GABA signaling pathway are likely expressed in this system. GABA signaling is initiated by the activation of either ionotropic receptors (GABAA and GABAC) or metabotropic receptors (GABAB) while it is terminated by the re-uptake of GABA through transporters (GATs).
Receptor Polymorphism and Genomic Structure Interact to Shape Bitter Taste Perception  [PDF]
Natacha Roudnitzky?,Maik Behrens?,Anika Engel?,Susann Kohl?,Sophie Thalmann?,Sandra Hübner?,Kristina Lossow?,Stephen P. Wooding?,Wolfgang Meyerhof
PLOS Genetics , 2015, DOI: 10.1371/journal.pgen.1005530
Abstract: The ability to taste bitterness evolved to safeguard most animals, including humans, against potentially toxic substances, thereby leading to food rejection. Nonetheless, bitter perception is subject to individual variations due to the presence of genetic functional polymorphisms in bitter taste receptor (TAS2R) genes, such as the long-known association between genetic polymorphisms in TAS2R38 and bitter taste perception of phenylthiocarbamide. Yet, due to overlaps in specificities across receptors, such associations with a single TAS2R locus are uncommon. Therefore, to investigate more complex associations, we examined taste responses to six structurally diverse compounds (absinthin, amarogentin, cascarillin, grosheimin, quassin, and quinine) in a sample of the Caucasian population. By sequencing all bitter receptor loci, inferring long-range haplotypes, mapping their effects on phenotype variation, and characterizing functionally causal allelic variants, we deciphered at the molecular level how a subjects’ genotype for the whole-family of TAS2R genes shapes variation in bitter taste perception. Within each haplotype block implicated in phenotypic variation, we provided evidence for at least one locus harboring functional polymorphic alleles, e.g. one locus for sensitivity to amarogentin, one of the most bitter natural compounds known, and two loci for sensitivity to grosheimin, one of the bitter compounds of artichoke. Our analyses revealed also, besides simple associations, complex associations of bitterness sensitivity across TAS2R loci. Indeed, even if several putative loci harbored both high- and low-sensitivity alleles, phenotypic variation depended on linkage between these alleles. When sensitive alleles for bitter compounds were maintained in the same linkage phase, genetically driven perceptual differences were obvious, e.g. for grosheimin. On the contrary, when sensitive alleles were in opposite phase, only weak genotype-phenotype associations were seen, e.g. for absinthin, the bitter principle of the beverage absinth. These findings illustrate the extent to which genetic influences on taste are complex, yet arise from both receptor activation patterns and linkage structure among receptor genes.
Bitter Taste Receptors Influence Glucose Homeostasis  [PDF]
Cedrick D. Dotson, Lan Zhang, Hong Xu, Yu-Kyong Shin, Stephan Vigues, Sandra H. Ott, Amanda E. T. Elson, Hyun Jin Choi, Hillary Shaw, Josephine M. Egan, Braxton D. Mitchell, Xiaodong Li, Nanette I. Steinle, Steven D. Munger
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003974
Abstract: TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. These receptors are also expressed in subsets of cells within the mammalian gastrointestinal tract, where they mediate nutrient assimilation and endocrine responses. For example, sweeteners stimulate taste receptors on the surface of gut enteroendocrine L cells to elicit an increase in intracellular Ca2+ and secretion of the incretin hormone glucagon-like peptide-1 (GLP-1), an important modulator of insulin biosynthesis and secretion. Because of the importance of taste receptors in the regulation of food intake and the alimentary responses to chemostimuli, we hypothesized that differences in taste receptor efficacy may impact glucose homeostasis. To address this issue, we initiated a candidate gene study within the Amish Family Diabetes Study and assessed the association of taste receptor variants with indicators of glucose dysregulation, including a diagnosis of type 2 diabetes mellitus and high levels of blood glucose and insulin during an oral glucose tolerance test. We report that a TAS2R haplotype is associated with altered glucose and insulin homeostasis. We also found that one SNP within this haplotype disrupts normal responses of a single receptor, TAS2R9, to its cognate ligands ofloxacin, procainamide and pirenzapine. Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease.
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