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• 41. [Article] Insulin-like Growth Factor Pathway Described in <i>Austrofundulus limnaeus</i> Diapause and Escape Embryos

  Development in the annual killifish Austrofundulus limnaeus can follow two distinct developmental trajectories. Typical development includes the entrance of embryos into a state of metabolic and developmental ...

  Citation × Citation Citation Abstract Copy Title: Insulin-like Growth Factor Pathway Described in <i>Austrofundulus limnaeus</i> Diapause and Escape Embryos Author: Woll, Steven Cody Year: 2016 Development in the annual killifish Austrofundulus limnaeus can follow two distinct developmental trajectories. Typical development includes the entrance of embryos into a state of metabolic and developmental arrest termed diapause. Alternately, embryos can escape diapause and develop directly without pause. These two trajectories are characterized by differences in the rate and timing of developmental, morphological, and physiological traits. Insulin and Insulin-like growth factor (IGF) signaling (IIS) is known to regulate entrance into diapause in a variety of invertebrates. In this thesis I explore the possible role of IGFs in the regulation of development and diapause in embryos of A. limnaeus. Here I report stage-specific expression of IGF-I and II proteins and their associated mRNA transcripts. Patterns of IGF-I protein expression are consistent with IGF signaling playing a major role in supporting the escape trajectory. In addition, treatment of embryos with a potent inhibitor of the IGF-I receptor (IGF1R) mimics the diapause developmental pattern even under conditions that should favor direct development. Evaluation of mRNA gene expression patterns in the two developmental trajectories suggests a role for IGF-I signaling through the RAS-MAPK-ERK pathway, which may be promoting the escape phenotype. Additionally, IGF-I activity may be enhanced in escape trajectory embryos though upregulation of IGF binding protein 2 (IGFBP-2) mRNA. These data suggest a major role for IGF signaling in the promotion of the escape trajectory, and thus we predict that specific mechanisms are in place in diapause-bound embryos that block IGF signaling and thus promote entrance into diapause. The data presented here suggest that blocking IGF signaling is critical for induction of diapause, but also suggests that other signaling pathways are likely also at play. Other pathways such at the TGF-beta signaling molecules and SMAD pathway, may also be involved in the direct regulation of the diapause phenotype, as has been shown for other animal models of developmental arrest. Title: Insulin-like Growth Factor Pathway Described in <i>Austrofundulus limnaeus</i> Diapause and Escape Embryos Author: Woll, Steven Cody Year: 2016 Development in the annual killifish Austrofundulus limnaeus can follow two distinct developmental trajectories. Typical development includes the entrance of embryos into a state of metabolic and developmental arrest termed diapause. Alternately, embryos can escape diapause and develop directly without pause. These two trajectories are characterized by differences in the rate and timing of developmental, morphological, and physiological traits. Insulin and Insulin-like growth factor (IGF) signaling (IIS) is known to regulate entrance into diapause in a variety of invertebrates. In this thesis I explore the possible role of IGFs in the regulation of development and diapause in embryos of A. limnaeus. Here I report stage-specific expression of IGF-I and II proteins and their associated mRNA transcripts. Patterns of IGF-I protein expression are consistent with IGF signaling playing a major role in supporting the escape trajectory. In addition, treatment of embryos with a potent inhibitor of the IGF-I receptor (IGF1R) mimics the diapause developmental pattern even under conditions that should favor direct development. Evaluation of mRNA gene expression patterns in the two developmental trajectories suggests a role for IGF-I signaling through the RAS-MAPK-ERK pathway, which may be promoting the escape phenotype. Additionally, IGF-I activity may be enhanced in escape trajectory embryos though upregulation of IGF binding protein 2 (IGFBP-2) mRNA. These data suggest a major role for IGF signaling in the promotion of the escape trajectory, and thus we predict that specific mechanisms are in place in diapause-bound embryos that block IGF signaling and thus promote entrance into diapause. The data presented here suggest that blocking IGF signaling is critical for induction of diapause, but also suggests that other signaling pathways are likely also at play. Other pathways such at the TGF-beta signaling molecules and SMAD pathway, may also be involved in the direct regulation of the diapause phenotype, as has been shown for other animal models of developmental arrest. Close

• 42. [Article] Loss of Cul3 in Primary Fibroblasts

  DNA holds the essence of life, and interpreting it can give us clues about cell dynamics. Using retrospective analysis of cell processes, such as protein production and degradation, we try to answer some ...

  Citation × Citation Citation Abstract Copy Title: Loss of Cul3 in Primary Fibroblasts Author: Hanna, Paula Year: 2013 DNA holds the essence of life, and interpreting it can give us clues about cell dynamics. Using retrospective analysis of cell processes, such as protein production and degradation, we try to answer some basic questions, taking advantage of cells being the fundamental units of life. Disruption of these complex processes results in abnormality, dysfunction, and eventually cell death. Cul3 is an essential enzyme that regulates the levels of proteins that in turn regulate transitions between different cell cycle stages. Cell cycle is a description of progressive order of events that lead to cell division. When the Cul3 gene is knocked out in cells of living organisms, some cells undergo apoptosis, or programmed cell death. This research focuses on the role of Cul3 in regulation of cell cycle transitions with a particular interest in how cells that lose Cul3 enter into the apoptotic pathway. The experimental system utilizes a special allele of Cul3 that was constructed in the lab and contains flanking DNA signals for a recombinase called Cre. When expressed, the Cre recombinase knocks out the Cul3 gene. Cells that have lost the gene are then monitored and analyzed for DNA breaks. We introduced the Cre gene using retroviral infection of primary fibroblasts containing the Cul3 special allele. This virus also expresses a special form of green fluorescent protein that allows us to identify cells that lost the Cul3 gene. As part of the experimental design, controls, which are cells that cannot delete the Cul3 gene and viruses that only express the green indicator protein, are included. Faculty Mentor: Jeffrey Singer Title: Loss of Cul3 in Primary Fibroblasts Author: Hanna, Paula Year: 2013 DNA holds the essence of life, and interpreting it can give us clues about cell dynamics. Using retrospective analysis of cell processes, such as protein production and degradation, we try to answer some basic questions, taking advantage of cells being the fundamental units of life. Disruption of these complex processes results in abnormality, dysfunction, and eventually cell death. Cul3 is an essential enzyme that regulates the levels of proteins that in turn regulate transitions between different cell cycle stages. Cell cycle is a description of progressive order of events that lead to cell division. When the Cul3 gene is knocked out in cells of living organisms, some cells undergo apoptosis, or programmed cell death. This research focuses on the role of Cul3 in regulation of cell cycle transitions with a particular interest in how cells that lose Cul3 enter into the apoptotic pathway. The experimental system utilizes a special allele of Cul3 that was constructed in the lab and contains flanking DNA signals for a recombinase called Cre. When expressed, the Cre recombinase knocks out the Cul3 gene. Cells that have lost the gene are then monitored and analyzed for DNA breaks. We introduced the Cre gene using retroviral infection of primary fibroblasts containing the Cul3 special allele. This virus also expresses a special form of green fluorescent protein that allows us to identify cells that lost the Cul3 gene. As part of the experimental design, controls, which are cells that cannot delete the Cul3 gene and viruses that only express the green indicator protein, are included. Faculty Mentor: Jeffrey Singer Close

• 43. [Article] New Product Introduction of Telecommunication Companies

  Since deregulation of industry in 1983, telecommunication companies have had to manage product development in an environment with major changes in technology, ongoing regulation, and a changing competitive ...

  Citation × Citation Citation Abstract Copy Title: New Product Introduction of Telecommunication Companies Author: Cooper, Mel Year: 2012 Since deregulation of industry in 1983, telecommunication companies have had to manage product development in an environment with major changes in technology, ongoing regulation, and a changing competitive landscape. Few industries have had to navigate so many concurrent changes as the telecommunications industry. This report seeks to evaluate how the major telecommunications suppliers successful package and introduce new products in an environment with limited regulation changing technologies. An evaluation of voice and data products introduced by AT&T, Sprint and MCI (later WorldCom, Verizon) reveal how carriers maintain profit margins despite falling prices in a highly competitive environment. Few industries could claim to have created a science of deceptive pricing policies as successfully as the telecommunications industry. Through a series of proverbial shell games, few customers have the savvy to understand, telecommunications carriers take advantage of falling service delivery costs as a result of technology improvements, create complex multi-variable pricing schemes that only appear to pass along the technology savings to their customers. Furthermore, in what many would call conclusion among the carriers, customers thinking that competitive bidding ensures the most competitive price are collectively mislead by all bidders. This report sheds light on the product development and service introduction process of telecommunications suppliers. It should be noted that while data is available regarding regulatory information, and to a limited degree the product development process referenced herein, this report contains primary research based on an analysis of custom telecommunications contracts filled with the FCC from 1996 to the present. Title: New Product Introduction of Telecommunication Companies Author: Cooper, Mel Year: 2012 Since deregulation of industry in 1983, telecommunication companies have had to manage product development in an environment with major changes in technology, ongoing regulation, and a changing competitive landscape. Few industries have had to navigate so many concurrent changes as the telecommunications industry. This report seeks to evaluate how the major telecommunications suppliers successful package and introduce new products in an environment with limited regulation changing technologies. An evaluation of voice and data products introduced by AT&T, Sprint and MCI (later WorldCom, Verizon) reveal how carriers maintain profit margins despite falling prices in a highly competitive environment. Few industries could claim to have created a science of deceptive pricing policies as successfully as the telecommunications industry. Through a series of proverbial shell games, few customers have the savvy to understand, telecommunications carriers take advantage of falling service delivery costs as a result of technology improvements, create complex multi-variable pricing schemes that only appear to pass along the technology savings to their customers. Furthermore, in what many would call conclusion among the carriers, customers thinking that competitive bidding ensures the most competitive price are collectively mislead by all bidders. This report sheds light on the product development and service introduction process of telecommunications suppliers. It should be noted that while data is available regarding regulatory information, and to a limited degree the product development process referenced herein, this report contains primary research based on an analysis of custom telecommunications contracts filled with the FCC from 1996 to the present. Close

• 44. [Article] The metabolic cost of behavioral thermoregulation of body temperature in the northern alligator lizard Gerrhonotus coeruleus, and how it affects the classical concept of eurythermality

  The effect of total metabolic cost expenditures on the precision of behavioral thermoregulation was investigated for the purportedly eurythermic Northern Alligator lizard (Gerrhonotus coeruleus). An operant ...

  Citation × Citation Citation Abstract Copy Title: The metabolic cost of behavioral thermoregulation of body temperature in the northern alligator lizard Gerrhonotus coeruleus, and how it affects the classical concept of eurythermality Author: Campbell, James Dudley Year: 1981 The effect of total metabolic cost expenditures on the precision of behavioral thermoregulation was investigated for the purportedly eurythermic Northern Alligator lizard (Gerrhonotus coeruleus). An operant apparatus was designed to test metabolic output at different heat reinforcement magnitudes. The mean TB reflected in each trial was positively correlated to the length of reinforcement. The shuttle rate during each trial was inversely correlated to the length of reinforcement. The standard deviation and total metabolic costs did not vary significantly between trials undertaken at the same ambient temperature. Eurythermality in G. coeruleus is caused by fluctuations in preferred body temperature and not by fluctuations around this temperature. The metabolic cost of behavioral thermoregulation did not change with corresponding changes in reinforcement magnitude. This indicates that eurythermality is the recorded effect of lizards behaviorally regulating to different TB in a stenothermic manner, rather than of random TB fluctuations in a wide range of normal activity (the classical view of eurythermality). Title: The metabolic cost of behavioral thermoregulation of body temperature in the northern alligator lizard Gerrhonotus coeruleus, and how it affects the classical concept of eurythermality Author: Campbell, James Dudley Year: 1981 The effect of total metabolic cost expenditures on the precision of behavioral thermoregulation was investigated for the purportedly eurythermic Northern Alligator lizard (Gerrhonotus coeruleus). An operant apparatus was designed to test metabolic output at different heat reinforcement magnitudes. The mean TB reflected in each trial was positively correlated to the length of reinforcement. The shuttle rate during each trial was inversely correlated to the length of reinforcement. The standard deviation and total metabolic costs did not vary significantly between trials undertaken at the same ambient temperature. Eurythermality in G. coeruleus is caused by fluctuations in preferred body temperature and not by fluctuations around this temperature. The metabolic cost of behavioral thermoregulation did not change with corresponding changes in reinforcement magnitude. This indicates that eurythermality is the recorded effect of lizards behaviorally regulating to different TB in a stenothermic manner, rather than of random TB fluctuations in a wide range of normal activity (the classical view of eurythermality). Close

• 45. [Article] The Regulation of Insulin-like Growth Factor 1 by Growth Hormone via Stat5b

  The growth hormone (GH) and insulin-like factor 1 (IGF-1) growth axis is integral to growth, metabolism and tissue repair. This pathway involves binding of GH to the GH receptor and activation of the transcription ...

  Citation × Citation Citation Abstract Copy Title: The Regulation of Insulin-like Growth Factor 1 by Growth Hormone via Stat5b Author: Morrison, Tiffany Year: 2012 The growth hormone (GH) and insulin-like factor 1 (IGF-1) growth axis is integral to growth, metabolism and tissue repair. This pathway involves binding of GH to the GH receptor and activation of the transcription factor, Stat5b, leading to nuclear transclocation, interaction with DNA binding sites in chromatin and stimulation of IGF-1 transcription. Stat5b binding sites have been determined experimentally by previous research but are all found far from the IGF-1 promoters and the mechanism by which Stat5b binding initiates IGF-1 gene transcription is currently unknown. Since no system for studying this process currently exists, the goal of this project is to create a cell-based transcriptional test system by placing the rat IGF-1 locus in the form of a linearized bacterial artificial chromosome (BAC) into mammalian cell line. The transgene then will be studied for GH regulation, Stat5b binding to specific DNA sequences, and the long distance interactions between Stat5b binding sites and the IGF-1 gene promoters that are for activating IGF-1 gene transcription. If successful, this project will help to answer fundamental questions about the GH IGF-1 growth axis, more specifically the role of Stat5b. Title: The Regulation of Insulin-like Growth Factor 1 by Growth Hormone via Stat5b Author: Morrison, Tiffany Year: 2012 The growth hormone (GH) and insulin-like factor 1 (IGF-1) growth axis is integral to growth, metabolism and tissue repair. This pathway involves binding of GH to the GH receptor and activation of the transcription factor, Stat5b, leading to nuclear transclocation, interaction with DNA binding sites in chromatin and stimulation of IGF-1 transcription. Stat5b binding sites have been determined experimentally by previous research but are all found far from the IGF-1 promoters and the mechanism by which Stat5b binding initiates IGF-1 gene transcription is currently unknown. Since no system for studying this process currently exists, the goal of this project is to create a cell-based transcriptional test system by placing the rat IGF-1 locus in the form of a linearized bacterial artificial chromosome (BAC) into mammalian cell line. The transgene then will be studied for GH regulation, Stat5b binding to specific DNA sequences, and the long distance interactions between Stat5b binding sites and the IGF-1 gene promoters that are for activating IGF-1 gene transcription. If successful, this project will help to answer fundamental questions about the GH IGF-1 growth axis, more specifically the role of Stat5b. Close

• 46. [Article] Innovation and Development of Lipsticks

  The history of the innovation and development of the lipstick started since 2500-1000 BC. Then it was incrementally developed through the years after. Obviously, formula was the primary applicator considered ...

  Citation × Citation Citation Abstract Copy Title: Innovation and Development of Lipsticks Author: Banchongraksa, Bhawinee Year: 2017 The history of the innovation and development of the lipstick started since 2500-1000 BC. Then it was incrementally developed through the years after. Obviously, formula was the primary applicator considered as the innovation of lipsticks. Its development basically driven by failures, user-demands, technologies, social trends and social regulations. The innovation of its pigments, ingredients, shape and packaging were invented based on those drivers. Nowadays, development of modern lipsticks seems not focus primarily on the pigments but other applicators such as transferred-resistance and lip protection. This paper illustrates that factors such as user-demands, social-trend, and social regulations significantly drive innovation of lipstick in the years before industry revolution of late 19th century while the technology advancement could be the factor which significantly drive lipstick innovation in the years after industrial revolution. Also, this paper provides a case of mass customization in lipstick business which now, seems to be the most advancement in the cosmetic business by focusing in particular brand, BITE who has been successful in customization services. Title: Innovation and Development of Lipsticks Author: Banchongraksa, Bhawinee Year: 2017 The history of the innovation and development of the lipstick started since 2500-1000 BC. Then it was incrementally developed through the years after. Obviously, formula was the primary applicator considered as the innovation of lipsticks. Its development basically driven by failures, user-demands, technologies, social trends and social regulations. The innovation of its pigments, ingredients, shape and packaging were invented based on those drivers. Nowadays, development of modern lipsticks seems not focus primarily on the pigments but other applicators such as transferred-resistance and lip protection. This paper illustrates that factors such as user-demands, social-trend, and social regulations significantly drive innovation of lipstick in the years before industry revolution of late 19th century while the technology advancement could be the factor which significantly drive lipstick innovation in the years after industrial revolution. Also, this paper provides a case of mass customization in lipstick business which now, seems to be the most advancement in the cosmetic business by focusing in particular brand, BITE who has been successful in customization services. Close

• 47. [Article] Non-canonical Binding of Calmodulin to Aquaporin-0: Implications for Channel Regulation

  Aquaporins (AQPs) are a family of ubiquitous membrane channels that conduct water across cell membranes. AQPs form homo-tetramers containing four functional and independent water pores. Aquaporin-0 (AQP0) ...

  Citation × Citation Citation Abstract Copy Title: Non-canonical Binding of Calmodulin to Aquaporin-0: Implications for Channel Regulation Author: Reichow, Steve, Gonen, Tamir Year: 2008 Aquaporins (AQPs) are a family of ubiquitous membrane channels that conduct water across cell membranes. AQPs form homo-tetramers containing four functional and independent water pores. Aquaporin-0 (AQP0) is expressed in the eye lens where its water permeability is regulated by calmodulin (CaM). Here we use a combination of biochemical methods and NMR spectroscopy to probe the interaction between AQP0 and CaM. We show CaM binds the AQP0 C-terminal domain in a calcium dependent manner. We demonstrate that only two CaM molecules bind a single AQP0 tetramer in a non-canonical fashion, suggesting a form of co-operativity between AQP0 monomers. Based on these results, we derive a structural model of the AQP0/CaM complex, which suggests CaM may be inhibitory to channel permeability by capping the vestibules of two monomers within the AQP0 tetramer. Finally, phosphorylation within AQP0’s CaM binding domain inhibits the AQP0/ CaM interaction suggesting a temporal regulatory mechanism for complex formation. Title: Non-canonical Binding of Calmodulin to Aquaporin-0: Implications for Channel Regulation Author: Reichow, Steve, Gonen, Tamir Year: 2008 Aquaporins (AQPs) are a family of ubiquitous membrane channels that conduct water across cell membranes. AQPs form homo-tetramers containing four functional and independent water pores. Aquaporin-0 (AQP0) is expressed in the eye lens where its water permeability is regulated by calmodulin (CaM). Here we use a combination of biochemical methods and NMR spectroscopy to probe the interaction between AQP0 and CaM. We show CaM binds the AQP0 C-terminal domain in a calcium dependent manner. We demonstrate that only two CaM molecules bind a single AQP0 tetramer in a non-canonical fashion, suggesting a form of co-operativity between AQP0 monomers. Based on these results, we derive a structural model of the AQP0/CaM complex, which suggests CaM may be inhibitory to channel permeability by capping the vestibules of two monomers within the AQP0 tetramer. Finally, phosphorylation within AQP0’s CaM binding domain inhibits the AQP0/ CaM interaction suggesting a temporal regulatory mechanism for complex formation. Close

• 48. [Article] Field Observations of the Developing Legal Recreational Cannabis Economy in Washington State

  Background Washington State legalized the sale of recreational cannabis in 2012. This paper describes the unfolding of the market regulatory regime in an eastern portion of the state, including field descriptions ...

  Citation × Citation Citation Abstract Copy Title: Field Observations of the Developing Legal Recreational Cannabis Economy in Washington State Author: Jensen, Eric L., Roussell, Aaron Year: 2016 Background Washington State legalized the sale of recreational cannabis in 2012. This paper describes the unfolding of the market regulatory regime in an eastern portion of the state, including field descriptions to illustrate the setting. Methods We made observations and conducted interviews of the local supply chain comprising a producer/processor, analytic facility, and retail establishments as well as querying the state director of the regulatory board. Results Interviews and observations of facilities suggest an overwhelming concern for black market diversion drives state regulatory efforts. The ongoing dialogue between market actors and the state has resulted in a more equitable distribution of profits at different stages in the process. State safety regulations have thus far been shifted to independent laboratories. Banks and insurance companies have slowly begun making inroads into the industry, despite federal prohibition. Conclusion The law was conceived as a social justice remedy, but the bulk of the legal and regulatory activity surrounds cannabis marketplace management. This has been characterized by concerns for black market diversion, producer/processor profits, and a hands-off approach to safety regulation. Minor cannabis violations as a pathway to criminal justice system involvement have been reduced substantially but disproportionate enforcement upon racial/ethnic minorities continues. Title: Field Observations of the Developing Legal Recreational Cannabis Economy in Washington State Author: Jensen, Eric L., Roussell, Aaron Year: 2016 Background Washington State legalized the sale of recreational cannabis in 2012. This paper describes the unfolding of the market regulatory regime in an eastern portion of the state, including field descriptions to illustrate the setting. Methods We made observations and conducted interviews of the local supply chain comprising a producer/processor, analytic facility, and retail establishments as well as querying the state director of the regulatory board. Results Interviews and observations of facilities suggest an overwhelming concern for black market diversion drives state regulatory efforts. The ongoing dialogue between market actors and the state has resulted in a more equitable distribution of profits at different stages in the process. State safety regulations have thus far been shifted to independent laboratories. Banks and insurance companies have slowly begun making inroads into the industry, despite federal prohibition. Conclusion The law was conceived as a social justice remedy, but the bulk of the legal and regulatory activity surrounds cannabis marketplace management. This has been characterized by concerns for black market diversion, producer/processor profits, and a hands-off approach to safety regulation. Minor cannabis violations as a pathway to criminal justice system involvement have been reduced substantially but disproportionate enforcement upon racial/ethnic minorities continues. Close

• 49. [Article] Travel and Parking Behavior in the United States

  This paper looks at the connection between the regulation of parking by cities, transit service levels, and travel and parking behavior in the United States. Travel behavior information comes from the ...

  Citation × Citation Citation Abstract Copy Title: Travel and Parking Behavior in the United States Author: Mildner, Gerard C., Strathman, James G., Bianco, Martha J. Year: 1996 This paper looks at the connection between the regulation of parking by cities, transit service levels, and travel and parking behavior in the United States. Travel behavior information comes from the 1990 Nationwide Personal Transportation Survey (NPTS) and the Federal Urban Mass Transportation Administration’s 1990 Section 15 Report. Data on the current state of parking programs in place in central business districts of the U.S. is identified through telephone interviews of local officials responsible for parking policies from the twenty cities identified in the NPTS. The travel behavior analyses and the data from the parking officials interviews were combined with data from the Federal Highway Administration’s Journey-to-Work data to group cities according to their parking policies, transit service, and ridership levels on a continuum of “Transit-Accommodating Cities” and “Auto-Accomodating Cities”. A key finding is that cities with interventionist parking policies, high parking prices and limited supply, frequent transit service, and a high probability that travelers will pay to park are the most likely to have high transit ridership figures. Title: Travel and Parking Behavior in the United States Author: Mildner, Gerard C., Strathman, James G., Bianco, Martha J. Year: 1996 This paper looks at the connection between the regulation of parking by cities, transit service levels, and travel and parking behavior in the United States. Travel behavior information comes from the 1990 Nationwide Personal Transportation Survey (NPTS) and the Federal Urban Mass Transportation Administration’s 1990 Section 15 Report. Data on the current state of parking programs in place in central business districts of the U.S. is identified through telephone interviews of local officials responsible for parking policies from the twenty cities identified in the NPTS. The travel behavior analyses and the data from the parking officials interviews were combined with data from the Federal Highway Administration’s Journey-to-Work data to group cities according to their parking policies, transit service, and ridership levels on a continuum of “Transit-Accommodating Cities” and “Auto-Accomodating Cities”. A key finding is that cities with interventionist parking policies, high parking prices and limited supply, frequent transit service, and a high probability that travelers will pay to park are the most likely to have high transit ridership figures. Close

• 50. [Article] Non-thiol reagents regulate ryanodine receptor function by redox interactions that modify reactive thiols

  The Ca(2+) release channel (CRC) from sarcoplasmic reticulum (SR) is rich in thiol groups, and their oxidation/- reduction by thiol reagents activates/inhibits the CRC. Most channel regulators are not ...

  Citation × Citation Citation Abstract Copy Title: Non-thiol reagents regulate ryanodine receptor function by redox interactions that modify reactive thiols Author: Marinov, Benjamin S., Olojo, Rotimi O., Xia, Ruohong, Abramson, Jonathan J. Year: 2007 The Ca(2+) release channel (CRC) from sarcoplasmic reticulum (SR) is rich in thiol groups, and their oxidation/- reduction by thiol reagents activates/inhibits the CRC. Most channel regulators are not thiol reagents, and the mechanism of their action is illusive. Here the authors show that many channel activators act as electron acceptors, while many channel inhibitors act as electron donors in free radical reactions. The channel activator, caffeine, and the CRC inhibitor, tetracaine, are shown to interact competitively, which suggests that there exists a common site(s) on the CRC, that integrates the donor/acceptor effects of ligands. Moreover, channel activators shift the redox potential of reactive thiols on the ryanodinereceptor (RyR) to more negative values and decrease the number of reactive thiols, while channel inhibitors shift the redox potential to more positive values and increase the number of reactive thiols. These observations suggest that thenon-thiol channel modulators shift the thiol-disulfide balance within CRC by transiently exchanging electrons with the Ca(2+) release protein. Title: Non-thiol reagents regulate ryanodine receptor function by redox interactions that modify reactive thiols Author: Marinov, Benjamin S., Olojo, Rotimi O., Xia, Ruohong, Abramson, Jonathan J. Year: 2007 The Ca(2+) release channel (CRC) from sarcoplasmic reticulum (SR) is rich in thiol groups, and their oxidation/- reduction by thiol reagents activates/inhibits the CRC. Most channel regulators are not thiol reagents, and the mechanism of their action is illusive. Here the authors show that many channel activators act as electron acceptors, while many channel inhibitors act as electron donors in free radical reactions. The channel activator, caffeine, and the CRC inhibitor, tetracaine, are shown to interact competitively, which suggests that there exists a common site(s) on the CRC, that integrates the donor/acceptor effects of ligands. Moreover, channel activators shift the redox potential of reactive thiols on the ryanodinereceptor (RyR) to more negative values and decrease the number of reactive thiols, while channel inhibitors shift the redox potential to more positive values and increase the number of reactive thiols. These observations suggest that thenon-thiol channel modulators shift the thiol-disulfide balance within CRC by transiently exchanging electrons with the Ca(2+) release protein. Close