The Battle of Mogadishu, more commonly referred to as “Black Hawk Down,” was one of the most controversial conflicts in the second half of the twentieth century. It left a lingering question in people’s minds: was it a success or a failure? While certainly there were many failures and casualties throughout the mission, based on a military definition, it was a clear cut success; Task Force Ranger (TFR) accomplished the objective of the mission, despite significant losses, by retrieving the two targets assigned them. Both the failures and successes of the mission, as well as the overarching Operation Restore Hope in Somalia, however, have impacted U.S. foreign policy and strategies for three presidential administrations. The question is not whether the events throughout the battle impacted foreign policy and strategy. Rather, the question is how significantly they were affected. Arguably one of the largest American special operations missions in recent history, the events of the battle have been thoroughly examined by the United States government and military in order to effect change in both realms. Examples found in places such as Rwanda, Bosnia, and Darfur point to a refusal by the United States to commit ground troops in an unstable situation, providing air support at a maximum. Following the foreign policy failure within Somalia in the early 1990s, except for the situation in Iraq/ Afghanistan, the United States has refused to act as the global police force it was so well known to be in the 20th century. This paper will attempt to prove that both the successes and failures of Operation Restore Hope and Operation Gothic Serpent directly caused this change in foreign policy.
{"title":"The Successes and Failures of the Battle of Mogadishu and Its Effects on U.S. Foreign Policy","authors":"Philip B Dotson","doi":"10.15385/JCH.2016.1.1.3","DOIUrl":"https://doi.org/10.15385/JCH.2016.1.1.3","url":null,"abstract":"The Battle of Mogadishu, more commonly referred to as “Black Hawk Down,” was one of the most controversial conflicts in the second half of the twentieth century. It left a lingering question in people’s minds: was it a success or a failure? While certainly there were many failures and casualties throughout the mission, based on a military definition, it was a clear cut success; Task Force Ranger (TFR) accomplished the objective of the mission, despite significant losses, by retrieving the two targets assigned them. Both the failures and successes of the mission, as well as the overarching Operation Restore Hope in Somalia, however, have impacted U.S. foreign policy and strategies for three presidential administrations. The question is not whether the events throughout the battle impacted foreign policy and strategy. Rather, the question is how significantly they were affected. Arguably one of the largest American special operations missions in recent history, the events of the battle have been thoroughly examined by the United States government and military in order to effect change in both realms. Examples found in places such as Rwanda, Bosnia, and Darfur point to a refusal by the United States to commit ground troops in an unstable situation, providing air support at a maximum. Following the foreign policy failure within Somalia in the early 1990s, except for the situation in Iraq/ Afghanistan, the United States has refused to act as the global police force it was so well known to be in the 20th century. This paper will attempt to prove that both the successes and failures of Operation Restore Hope and Operation Gothic Serpent directly caused this change in foreign policy.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88587073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract This paper explores the concept of impassibility in the early Greek apologists and Irenaeus. The paper focuses on impassibility as related to emotion in the divine nature, and individually examines Justin Martyr, Athenagoras and Irenaeus. This paper attempts to present a nuanced and faithful interpretation of impassibility in these fathers contra the assumption that impassibility equates to static emotionlessness. The author argues that the early Greek fathers used impassibility as an apophatic qualifier tied to God's immutability, virtuousness, and status as creator and further used impassibility to indicate that God was not overwhelmed by passions like the pagan and gnostic deities. This thesis is substantiated by briefly noting the lexical and philosophical backgrounds of the terms for impassibility used by the early Greek fathers and by an individual examination of each of the fathers mentioned above.
{"title":"Emotions and the Divine Nature: Impassibility in the Greek Apologists and Irenaeus","authors":"J. Little","doi":"10.15385/JCH.2016.1.1.4","DOIUrl":"https://doi.org/10.15385/JCH.2016.1.1.4","url":null,"abstract":"Abstract This paper explores the concept of impassibility in the early Greek apologists and Irenaeus. The paper focuses on impassibility as related to emotion in the divine nature, and individually examines Justin Martyr, Athenagoras and Irenaeus. This paper attempts to present a nuanced and faithful interpretation of impassibility in these fathers contra the assumption that impassibility equates to static emotionlessness. The author argues that the early Greek fathers used impassibility as an apophatic qualifier tied to God's immutability, virtuousness, and status as creator and further used impassibility to indicate that God was not overwhelmed by passions like the pagan and gnostic deities. This thesis is substantiated by briefly noting the lexical and philosophical backgrounds of the terms for impassibility used by the early Greek fathers and by an individual examination of each of the fathers mentioned above.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90185436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This paper discusses the orator and the audience's roles in both Aristotle's rhetoric and contemporary rhetoric. Moreover, it argues that technical communicators should revive Aristotle's rhetoric because it allows them to take ownership of their work.
{"title":"Aesop’s Trumpeter, Aristotle’s Orator, and the Technical Communicator","authors":"Ruth E. Towne","doi":"10.15385/JCH.2016.1.1.6","DOIUrl":"https://doi.org/10.15385/JCH.2016.1.1.6","url":null,"abstract":"This paper discusses the orator and the audience's roles in both Aristotle's rhetoric and contemporary rhetoric. Moreover, it argues that technical communicators should revive Aristotle's rhetoric because it allows them to take ownership of their work.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78682982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-11-22DOI: 10.15385/JCH.2016.1.1.10
E. M. Parsons
Abstract This article applies George Canguilhem’s notion of monster theory as a method for cultural analysis to the analysis of literature. It argues that monster theory provides one accurate view of Japanese contemporary culture as it is depicted in literature, and that observing the relationship of artists and writers to the monsters they depict can lead to a valid hypothesis about the artist’s view of culture. Using this hypothesis as a theoretical framework, the article then analyzes The Taste of Tea, a contemporary film by Japanese director Katsuhito Ishii, in terms of monster theory. It concludes that monster theory vindicates the role of the artist as a cultural contributor because the artist is in a perfect position to interpret or mediate cultural anxiety and the perception of contemporary society by controlling the depiction of the monstrous.
{"title":"“Drawing Is Where The Joy Is”: Cultural Anxiety, the Monstrous Fantastic, and the Artist as Mediator in Katsuhito Ishii’s The Taste Of Tea","authors":"E. M. Parsons","doi":"10.15385/JCH.2016.1.1.10","DOIUrl":"https://doi.org/10.15385/JCH.2016.1.1.10","url":null,"abstract":"Abstract This article applies George Canguilhem’s notion of monster theory as a method for cultural analysis to the analysis of literature. It argues that monster theory provides one accurate view of Japanese contemporary culture as it is depicted in literature, and that observing the relationship of artists and writers to the monsters they depict can lead to a valid hypothesis about the artist’s view of culture. Using this hypothesis as a theoretical framework, the article then analyzes The Taste of Tea, a contemporary film by Japanese director Katsuhito Ishii, in terms of monster theory. It concludes that monster theory vindicates the role of the artist as a cultural contributor because the artist is in a perfect position to interpret or mediate cultural anxiety and the perception of contemporary society by controlling the depiction of the monstrous.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77091077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This paper explores the present state of institutional discipline regarding sexual assaults on campus and the impact of the April 4, 2011 “Dear Colleague Letter” (DCL) issued by the Office for Civil Rights of the Department of Education on this problem. The paper then discusses the applicable Title IX standards and the procedural due process rights for the accused in campus sexual assault cases. The paper explores colleges’ responses to the DCL and means for redress for the accused under Title IX. The author argues that the DCL improperly incentivizes colleges to convict the accused, and suggests that cases of sexual assault on university campuses should be referred to courts to secure proper due process rights for both the accused and the accuser.
{"title":"Campus Sexual Misconduct Due Process Protections","authors":"C. Kirkpatrick","doi":"10.15385/JCH.2016.1.1.2","DOIUrl":"https://doi.org/10.15385/JCH.2016.1.1.2","url":null,"abstract":"This paper explores the present state of institutional discipline regarding sexual assaults on campus and the impact of the April 4, 2011 “Dear Colleague Letter” (DCL) issued by the Office for Civil Rights of the Department of Education on this problem. The paper then discusses the applicable Title IX standards and the procedural due process rights for the accused in campus sexual assault cases. The paper explores colleges’ responses to the DCL and means for redress for the accused under Title IX. The author argues that the DCL improperly incentivizes colleges to convict the accused, and suggests that cases of sexual assault on university campuses should be referred to courts to secure proper due process rights for both the accused and the accuser.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74812186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-09-30DOI: 10.1080/19336950.2016.1243190
C. Villalba-Galea
ABSTRACT Ion channels constitute a superfamily of membrane proteins found in all living creatures. Their activity allows fast translocation of ions across the plasma membrane down the ion's transmembrane electrochemical gradient, resulting in a difference in electrical potential across the plasma membrane, known as the membrane potential. A group within this superfamily, namely voltage-gated channels, displays activity that is sensitive to the membrane potential. The activity of voltage-gated channels is controlled by the membrane potential, while the membrane potential is changed by these channels' activity. This interplay produces variations in the membrane potential that have evolved into electrical signals in many organisms. These signals are essential for numerous biological processes, including neuronal activity, insulin release, muscle contraction, fertilization and many others. In recent years, the activity of the voltage-gated channels has been observed not to follow a simple relationship with the membrane potential. Instead, it has been shown that the activity of voltage-gated channel displays hysteresis. In fact, a growing number of evidence have demonstrated that the voltage dependence of channel activity is dynamically modulated by activity itself. In spite of the great impact that this property can have on electrical signaling, hysteresis in voltage-gated channels is often overlooked. Addressing this issue, this review provides examples of voltage-gated ion channels displaying hysteretic behavior. Further, this review will discuss how Dynamic Voltage Dependence in voltage-gated channels can have a physiological role in electrical signaling. Furthermore, this review will elaborate on the current thoughts on the mechanism underlying hysteresis in voltage-gated channels.
{"title":"Hysteresis in voltage-gated channels","authors":"C. Villalba-Galea","doi":"10.1080/19336950.2016.1243190","DOIUrl":"https://doi.org/10.1080/19336950.2016.1243190","url":null,"abstract":"ABSTRACT Ion channels constitute a superfamily of membrane proteins found in all living creatures. Their activity allows fast translocation of ions across the plasma membrane down the ion's transmembrane electrochemical gradient, resulting in a difference in electrical potential across the plasma membrane, known as the membrane potential. A group within this superfamily, namely voltage-gated channels, displays activity that is sensitive to the membrane potential. The activity of voltage-gated channels is controlled by the membrane potential, while the membrane potential is changed by these channels' activity. This interplay produces variations in the membrane potential that have evolved into electrical signals in many organisms. These signals are essential for numerous biological processes, including neuronal activity, insulin release, muscle contraction, fertilization and many others. In recent years, the activity of the voltage-gated channels has been observed not to follow a simple relationship with the membrane potential. Instead, it has been shown that the activity of voltage-gated channel displays hysteresis. In fact, a growing number of evidence have demonstrated that the voltage dependence of channel activity is dynamically modulated by activity itself. In spite of the great impact that this property can have on electrical signaling, hysteresis in voltage-gated channels is often overlooked. Addressing this issue, this review provides examples of voltage-gated ion channels displaying hysteretic behavior. Further, this review will discuss how Dynamic Voltage Dependence in voltage-gated channels can have a physiological role in electrical signaling. Furthermore, this review will elaborate on the current thoughts on the mechanism underlying hysteresis in voltage-gated channels.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85491001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-04-20DOI: 10.1080/19336950.2016.1168551
G. Bidaux, Anne-sophie Borowiec, N. Prevarskaya, D. Gordienko
ABSTRACT Recently, we reported the cloning and characterization of short isoform of the icilin-activated cold receptor TRPM8 channel in keratinocytes, dubbed eTRPM8. We demonstrated that eTRPM8 via fine tuning of the endoplasmic reticulum (ER) – mitochondria Ca2+ shuttling regulates mitochondrial ATP and superoxide (O2•-) production and, thereby, mediates control of epidermal homeostasis by mild cold. Here, we provide additional information explaining why eTRPM8 suppression and TRPM8 stimulation both inhibit keratinocyte growth. We also demonstrate that stimulation of eTRPM8 with icilin may give rise to sustained oscillatory responses. Furthermore, we show that ATP-induced cytosolic and mitochondrial Ca2+ responses are attenuated by eTRPM8 suppression. This suggests positive interplay between eTRPM8 and purinergic signaling pathways, what may serve to facilitate the ER-mitochondria Ca2+ shuttling. Finally, we demonstrate that cold (25°C) induces eTRPM8-dependent superoxide-mediated necrosis of keratinocytes. Altogether, these results are in line with our model of eTRPM8-mediated cold-dependent balance between keratinocyte proliferation and differentiation.
{"title":"Fine-tuning of eTRPM8 expression and activity conditions keratinocyte fate","authors":"G. Bidaux, Anne-sophie Borowiec, N. Prevarskaya, D. Gordienko","doi":"10.1080/19336950.2016.1168551","DOIUrl":"https://doi.org/10.1080/19336950.2016.1168551","url":null,"abstract":"ABSTRACT Recently, we reported the cloning and characterization of short isoform of the icilin-activated cold receptor TRPM8 channel in keratinocytes, dubbed eTRPM8. We demonstrated that eTRPM8 via fine tuning of the endoplasmic reticulum (ER) – mitochondria Ca2+ shuttling regulates mitochondrial ATP and superoxide (O2•-) production and, thereby, mediates control of epidermal homeostasis by mild cold. Here, we provide additional information explaining why eTRPM8 suppression and TRPM8 stimulation both inhibit keratinocyte growth. We also demonstrate that stimulation of eTRPM8 with icilin may give rise to sustained oscillatory responses. Furthermore, we show that ATP-induced cytosolic and mitochondrial Ca2+ responses are attenuated by eTRPM8 suppression. This suggests positive interplay between eTRPM8 and purinergic signaling pathways, what may serve to facilitate the ER-mitochondria Ca2+ shuttling. Finally, we demonstrate that cold (25°C) induces eTRPM8-dependent superoxide-mediated necrosis of keratinocytes. Altogether, these results are in line with our model of eTRPM8-mediated cold-dependent balance between keratinocyte proliferation and differentiation.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83227698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-04-11DOI: 10.1080/19336950.2016.1165375
Ken-ichi Nakajima, Min Zhao
Many motile cells, including epithelial cells, keratinocytes, leukocytes and cancer cells, can sense extracellular weak electric fields (EFs), and migrate directionally, a phenomenon termed electro...
{"title":"Concerted action of KCNJ15/Kir4.2 and intracellular polyamines in sensing physiological electric fields for galvanotaxis","authors":"Ken-ichi Nakajima, Min Zhao","doi":"10.1080/19336950.2016.1165375","DOIUrl":"https://doi.org/10.1080/19336950.2016.1165375","url":null,"abstract":"Many motile cells, including epithelial cells, keratinocytes, leukocytes and cancer cells, can sense extracellular weak electric fields (EFs), and migrate directionally, a phenomenon termed electro...","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86443458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-04-05DOI: 10.1080/19336950.2016.1172886
E. Kobrinsky, N. Soldatov
Tripartite anthrax toxin is composed of nontoxic edema factor (EF, calmodulin/Ca2C-dependent adenylate cyclase), lethal factor (LF, a zinc-dependent metallopeptidase cleaving mitogen activated protein kinases) and non-toxic PA (83 kDa). On release from the anthrax bacillus as monomers, they assemble into toxic complexes on the surface of host cells. According to the established mechanism of toxic effect, PA binds to the cell surface receptors and facilitates the translocation of a “lethal toxin” composed of LF and EF. Two PA receptors have been previously identified, including ATR/TEM8 (anthrax toxin receptor/tumor endothelial marker 8 ) and CMG2 (capillary morphogenesis protein 2 ). Mechanism of toxic effect is not well known, except that PA binds to the cell surface receptors and forms heptameric pores that are involved in translocation of the “lethal toxin." The formation of PA channels on the surface of a host target cell is a key step in the pathogenesis of anthrax. PA requires for binding a common von Willebrand factor A (integrin-like) inserted domain that contains MIDAS composed of DxSxSx59–79Tx12–23D, where x is any amino acid. The MIDAS domain is present in the accessory a2d-1 and a2d¡2 subunits of the Cav1 and Cav2 families of the calcium channel. Common features of a2d, ATR/TEM8 and CMG2 include an extracellular von Willebrand factor A domain and a single-pass transmembrane region. Because calcium channels are clustered in the plasma membrane, they suite well to co-localize the PA pores to allow for sufficient entry of anthrax toxin into the cells. Unlike ATR/TEM8 and CMG2, Cav1 and Cav2 calcium channels are present in a wide variety of cells of the body except cells of immune system and blood cells (although a2d is found in lymphocytes). Importantly, they are expressed in endothelial cells, keratinocytes and fibroblasts, which represent the primary locations for bacterial entry. Given the wide distribution of calcium channel a2d proteins, we hypothesize that the a2d subunit may interact with PA. This study presents the first experimental evidence suggesting such an interaction. The patch clamp study was carried out essentially as described earlier 8 with the recombinant human Cav1.2 calcium channels composed of the fluorescently labeled vascular/fibroblast pore-forming ECFPN-a1C,77 (z34815) subunit and accessory vascular b3 (X76555) subunit co-expressed with a2d¡1 (AAA51903) in Cos1 cells. In these studies we used PA-U7, the mutant of PA where the furin cleavage site was deleted. PA-U7 retains ability to bind to receptors but cannot be proteolytically activated. This property of PA-U7 is particularly useful for patch clamp experiments because PA-U7 is unable to form leak channels that would otherwise compromise the specificity of recordings and stability of patch clamp by generating a large non-selective leak current. It was found that PA-U7 inhibited the Ca2C current in a nM range (Fig. 1A). Although there are data that PA-U7 may ev
{"title":"Electrophysiological evidences of interaction between calcium channels and PA of anthrax","authors":"E. Kobrinsky, N. Soldatov","doi":"10.1080/19336950.2016.1172886","DOIUrl":"https://doi.org/10.1080/19336950.2016.1172886","url":null,"abstract":"Tripartite anthrax toxin is composed of nontoxic edema factor (EF, calmodulin/Ca2C-dependent adenylate cyclase), lethal factor (LF, a zinc-dependent metallopeptidase cleaving mitogen activated protein kinases) and non-toxic PA (83 kDa). On release from the anthrax bacillus as monomers, they assemble into toxic complexes on the surface of host cells. According to the established mechanism of toxic effect, PA binds to the cell surface receptors and facilitates the translocation of a “lethal toxin” composed of LF and EF. Two PA receptors have been previously identified, including ATR/TEM8 (anthrax toxin receptor/tumor endothelial marker 8 ) and CMG2 (capillary morphogenesis protein 2 ). Mechanism of toxic effect is not well known, except that PA binds to the cell surface receptors and forms heptameric pores that are involved in translocation of the “lethal toxin.\" The formation of PA channels on the surface of a host target cell is a key step in the pathogenesis of anthrax. PA requires for binding a common von Willebrand factor A (integrin-like) inserted domain that contains MIDAS composed of DxSxSx59–79Tx12–23D, where x is any amino acid. The MIDAS domain is present in the accessory a2d-1 and a2d¡2 subunits of the Cav1 and Cav2 families of the calcium channel. Common features of a2d, ATR/TEM8 and CMG2 include an extracellular von Willebrand factor A domain and a single-pass transmembrane region. Because calcium channels are clustered in the plasma membrane, they suite well to co-localize the PA pores to allow for sufficient entry of anthrax toxin into the cells. Unlike ATR/TEM8 and CMG2, Cav1 and Cav2 calcium channels are present in a wide variety of cells of the body except cells of immune system and blood cells (although a2d is found in lymphocytes). Importantly, they are expressed in endothelial cells, keratinocytes and fibroblasts, which represent the primary locations for bacterial entry. Given the wide distribution of calcium channel a2d proteins, we hypothesize that the a2d subunit may interact with PA. This study presents the first experimental evidence suggesting such an interaction. The patch clamp study was carried out essentially as described earlier 8 with the recombinant human Cav1.2 calcium channels composed of the fluorescently labeled vascular/fibroblast pore-forming ECFPN-a1C,77 (z34815) subunit and accessory vascular b3 (X76555) subunit co-expressed with a2d¡1 (AAA51903) in Cos1 cells. In these studies we used PA-U7, the mutant of PA where the furin cleavage site was deleted. PA-U7 retains ability to bind to receptors but cannot be proteolytically activated. This property of PA-U7 is particularly useful for patch clamp experiments because PA-U7 is unable to form leak channels that would otherwise compromise the specificity of recordings and stability of patch clamp by generating a large non-selective leak current. It was found that PA-U7 inhibited the Ca2C current in a nM range (Fig. 1A). Although there are data that PA-U7 may ev","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75446498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-03-30DOI: 10.1080/19336950.2016.1169744
Malini Ahuja, Soonhong Park, D. Shin, S. Muallem
TRP channels show remarkable diversity and influence many physiological functions. Most TRP channels are Ca2C permeable, reside in the plasma membrane and mediate Ca2C influx in response to various stimuli. However, members of the TRPML (mucolipins) subfamily reside in organelles and function as organellar channels. The subfamily includes three members and was established with the identification of TRPML1 as the protein mutated in the lysosomal storage disease (LSD) Mucolipidosis type IV (MLIV). All TRPML channels function as inward rectifying, Ca2C permeable cation channels and are activated by the organellar lipid PI(3,5)P2. TRPML1 is largely a lysosomal channel and is cleaved by lysosomal cathepsins, probably as an inactivation mechanism. TRPML3 is expressed mostly in early and late endosomes, while TRPML2 is found mainly in recycling endosomes. All TRPML channels function in organellar trafficking; nevertheless based on the knockout mouse phenotype, it appears that the roles of TRPML2 and TRPML3 are modest compared to TRPML1. TRPML3, a pH and NaC sensitive channel, has a role in autophagy, although knockout of TRPML3 has no obvious phenotype. The cellular role of TRPML2 is not well understood, but deletion results in a compromised immune response. Inactivating mutations of TRPML1 in humans and deletion of TRPML1 in mice result in LSD, indicating critical role of TRPML1 in lysosomal functions. Early studies demonstrated a role for TRPML1 in trafficking of early and late endosomes to and from the lysosomes, and in fusion of lysosomes with autophagosomes. Subsequent studies established TRPML1 as a lysosomal Ca2C release channel with a role in several lysosomal functions, including large particle phagocytosis, membrane repair and lysosomal trafficking to organelles and molecules designated for degradation. All the forms of lysosomal trafficking discussed above involve the constitutive trafficking pathway. Another important form of membrane trafficking is that associated with regulated exocytosis, such as secretion by acinar cells within exocrine glands, secretion by endocrine cells, and neurotransmitter release. Surprisingly, the role of the TRPML1 and the effect of any LSDs in regulated exocytosis have not been addressed before, although neurodegeneration is a common feature in all LSDs. In a recent study, we examined the role of TRPML1 in several forms of regulated exocytosis: Ca2C-dependent pancreatic exocytosis, cAMP-dependent salivary gland exocytosis, and neuronal exocytosis of glutamate. These studies showed that a major function of TRPML1 is to guard against uncontrolled fusion of the lysosomes with other intracellular organelles. The lysosome enlargement and increased lysosomal undigested content observed in LSDs indicate that the lysosomes do not lose their fusogenic potential in these diseases. This was revealed to be of major consequence in secretory cells containing fusogenic
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