Caroline A Cobine, E. Hannah, M. Zhu, H. E. Lyle, J. Rock, K. Sanders, S. Ward, K. Keef
The internal anal sphincter develops tone important for maintaining high anal pressure and continence. Controversy exists regarding the mechanisms underlying tone development. We examined the hypothesis that tone depends upon electrical slow waves (SWs) initiated in intramuscular interstitial cells of Cajal (ICC‐IM) by activation of Ca2+‐activated Cl− channels (ANO1, encoded by Ano1) and voltage‐dependent L‐type Ca2+ channels (CavL, encoded by Cacna1c). Measurement of membrane potential and contraction indicated that ANO1 and CavL have a central role in SW generation, phasic contractions and tone, independent of stretch. ANO1 expression was examined in wildtype and Ano1/+egfp mice with immunohistochemical techniques. Ano1 and Cacna1c expression levels were examined by quantitative PCR in fluorescence‐activated cell sorting. ICC‐IM were the predominant cell type expressing ANO1 and the most likely candidate for SW generation. SWs in ICC‐IM are proposed to conduct to smooth muscle where Ca2+ entry via CavL results in phasic activity that sums to produce tone.
{"title":"ANO1 in intramuscular interstitial cells of Cajal plays a key role in the generation of slow waves and tone in the internal anal sphincter","authors":"Caroline A Cobine, E. Hannah, M. Zhu, H. E. Lyle, J. Rock, K. Sanders, S. Ward, K. Keef","doi":"10.1113/JP273618","DOIUrl":"https://doi.org/10.1113/JP273618","url":null,"abstract":"The internal anal sphincter develops tone important for maintaining high anal pressure and continence. Controversy exists regarding the mechanisms underlying tone development. We examined the hypothesis that tone depends upon electrical slow waves (SWs) initiated in intramuscular interstitial cells of Cajal (ICC‐IM) by activation of Ca2+‐activated Cl− channels (ANO1, encoded by Ano1) and voltage‐dependent L‐type Ca2+ channels (CavL, encoded by Cacna1c). Measurement of membrane potential and contraction indicated that ANO1 and CavL have a central role in SW generation, phasic contractions and tone, independent of stretch. ANO1 expression was examined in wildtype and Ano1/+egfp mice with immunohistochemical techniques. Ano1 and Cacna1c expression levels were examined by quantitative PCR in fluorescence‐activated cell sorting. ICC‐IM were the predominant cell type expressing ANO1 and the most likely candidate for SW generation. SWs in ICC‐IM are proposed to conduct to smooth muscle where Ca2+ entry via CavL results in phasic activity that sums to produce tone.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"2008 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86233220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N. Shalabi, A. Cornachione, F. de Souza Leite, S. Vengallatore, D. Rassier
When a skeletal muscle is stretched while it contracts, the muscle produces a relatively higher force than the force from an isometric contraction at the same length: a phenomenon referred to as residual force enhancement. Residual force enhancement is puzzling because it cannot be directly explained by the classical force–length relationship and the sliding filament theory of contraction, the main paradigms in the muscle field. We used custom‐built instruments to measure residual force enhancement in skeletal myofibrils, and, for the first time, in cardiac myofibrils. Our data report that residual force enhancement is present in skeletal muscles, but not cardiac muscles, and is regulated by the different isoforms of the titin protein filaments.
{"title":"Residual force enhancement is regulated by titin in skeletal and cardiac myofibrils","authors":"N. Shalabi, A. Cornachione, F. de Souza Leite, S. Vengallatore, D. Rassier","doi":"10.1113/JP272983","DOIUrl":"https://doi.org/10.1113/JP272983","url":null,"abstract":"When a skeletal muscle is stretched while it contracts, the muscle produces a relatively higher force than the force from an isometric contraction at the same length: a phenomenon referred to as residual force enhancement. Residual force enhancement is puzzling because it cannot be directly explained by the classical force–length relationship and the sliding filament theory of contraction, the main paradigms in the muscle field. We used custom‐built instruments to measure residual force enhancement in skeletal myofibrils, and, for the first time, in cardiac myofibrils. Our data report that residual force enhancement is present in skeletal muscles, but not cardiac muscles, and is regulated by the different isoforms of the titin protein filaments.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78490887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Premature fetuses and babies are at greater risk of mortality and morbidity than their term counterparts. The underlying causes are multifactorial, but include exposure to hypoxia. Immaturity of organs and their functional control may impair the physiological defence responses to hypoxia and the preterm fetal responses, or lack thereof, to moderate hypoxia appear to support this concept. However, as this review demonstrates, despite immaturity, the preterm fetus responds to asphyxia in a qualitatively similar manner to that seen at term. This highlights the importance in understanding metabolism versus homeostatic threat when assessing fetal responses to adverse challenges such as hypoxia. Data are presented to show that the preterm fetal adaptation to asphyxia is triphasic in nature. Phase one represents the rapid institution of maximal defences, designed to maintain blood pressure and central perfusion at the expense of peripheral organs. Phase two is one of adaptive compensation. Controlled reperfusion partially offsets peripheral tissue oxygen debt, while maintaining sufficient vasoconstriction to limit the fall in perfusion. Phase three is about decompensation. Strikingly, the preterm fetus generally performs better during phases two and three, and can survive for longer without injury. Paradoxically, however, the ability to survive can lead to longer exposure to hypotension and hypoperfusion and thus potentially greater injury. The effects of fetal sex, inflammation and drugs on the triphasic adaptations are reviewed. Finally, the review highlights the need for more comprehensive studies to understand the complexity of perinatal physiology if we are to develop effective strategies to improve preterm outcomes.
{"title":"Sex, drugs and rock and roll: tales from preterm fetal life","authors":"L. Bennet","doi":"10.1113/JP272999","DOIUrl":"https://doi.org/10.1113/JP272999","url":null,"abstract":"Premature fetuses and babies are at greater risk of mortality and morbidity than their term counterparts. The underlying causes are multifactorial, but include exposure to hypoxia. Immaturity of organs and their functional control may impair the physiological defence responses to hypoxia and the preterm fetal responses, or lack thereof, to moderate hypoxia appear to support this concept. However, as this review demonstrates, despite immaturity, the preterm fetus responds to asphyxia in a qualitatively similar manner to that seen at term. This highlights the importance in understanding metabolism versus homeostatic threat when assessing fetal responses to adverse challenges such as hypoxia. Data are presented to show that the preterm fetal adaptation to asphyxia is triphasic in nature. Phase one represents the rapid institution of maximal defences, designed to maintain blood pressure and central perfusion at the expense of peripheral organs. Phase two is one of adaptive compensation. Controlled reperfusion partially offsets peripheral tissue oxygen debt, while maintaining sufficient vasoconstriction to limit the fall in perfusion. Phase three is about decompensation. Strikingly, the preterm fetus generally performs better during phases two and three, and can survive for longer without injury. Paradoxically, however, the ability to survive can lead to longer exposure to hypotension and hypoperfusion and thus potentially greater injury. The effects of fetal sex, inflammation and drugs on the triphasic adaptations are reviewed. Finally, the review highlights the need for more comprehensive studies to understand the complexity of perinatal physiology if we are to develop effective strategies to improve preterm outcomes.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"103 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80757436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N‐cadherin formed punctate adherens junctions (AJ) along the borders between vascular smooth muscle cells (VSMCs) in the pressurized rat superior cerebellar artery. The formation of N‐cadherin AJs in the vessel wall depends on the intraluminal pressure and was responsive to treatment with phenylephrine (PE) (10−5 m) and ACh (10−5 m). N‐cadherin‐coated beads were able to induce clustering of N‐cadherin‐enhanced green fluorescent protein (EGFP) on the plasma membrane of isolated VSMCs, whereas treatment with PE (10−5 m) or sodium nitroprusside (10−5 m) induced a significant increase or decrease in the N‐cadherin‐EGFP clustering, respectively. Application of pulling force (∼1 nN) to the N‐cadherin‐coated beads via an atomic force microscope induced a localized mechanical response from the VSMCs that opposed the pulling.
{"title":"N‐Cadherin, a novel and rapidly remodelling site involved in vasoregulation of small cerebral arteries","authors":"Zhe Sun, Min Li, Z. Li, M. Hill, G. Meininger","doi":"10.1113/JP272995","DOIUrl":"https://doi.org/10.1113/JP272995","url":null,"abstract":"N‐cadherin formed punctate adherens junctions (AJ) along the borders between vascular smooth muscle cells (VSMCs) in the pressurized rat superior cerebellar artery. The formation of N‐cadherin AJs in the vessel wall depends on the intraluminal pressure and was responsive to treatment with phenylephrine (PE) (10−5 m) and ACh (10−5 m). N‐cadherin‐coated beads were able to induce clustering of N‐cadherin‐enhanced green fluorescent protein (EGFP) on the plasma membrane of isolated VSMCs, whereas treatment with PE (10−5 m) or sodium nitroprusside (10−5 m) induced a significant increase or decrease in the N‐cadherin‐EGFP clustering, respectively. Application of pulling force (∼1 nN) to the N‐cadherin‐coated beads via an atomic force microscope induced a localized mechanical response from the VSMCs that opposed the pulling.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79252936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Astrocytes are the most common glial cells in the brain with fine processes and endfeet that intimately contact both neuronal synapses and the cerebral vasculature. They play an important role in mediating neurovascular coupling (NVC) via several astrocytic Ca2+‐dependent signalling pathways such as K+ release through BK channels, and the production and release of arachidonic acid metabolites. They are also involved in maintaining the resting tone of the cerebral vessels by releasing ATP and COX‐1 derivatives. Evidence also supports a role for astrocytes in maintaining blood pressure‐dependent change in cerebrovascular tone, and perhaps also in blood vessel‐to‐neuron signalling as posited by the ‘hemo‐neural hypothesis’. Thus, astrocytes are emerging as new stars in preserving the intricate balance between the high energy demand of active neurons and the supply of oxygen and nutrients from the blood by maintaining both resting blood flow and activity‐evoked changes therein. Following neuropathology, astrocytes become reactive and many of their key signalling mechanisms are altered, including those involved in NVC. Furthermore, as they can respond to changes in vascular pressure, cardiovascular diseases might exert previously unknown effects on the central nervous system by altering astrocyte function. This review discusses the role of astrocytes in neurovascular signalling in both physiology and pathology, and the impact of these findings on understanding BOLD‐fMRI signals.
{"title":"Binaural blood flow control by astrocytes: listening to synapses and the vasculature","authors":"Anusha Mishra","doi":"10.1113/JP270979","DOIUrl":"https://doi.org/10.1113/JP270979","url":null,"abstract":"Astrocytes are the most common glial cells in the brain with fine processes and endfeet that intimately contact both neuronal synapses and the cerebral vasculature. They play an important role in mediating neurovascular coupling (NVC) via several astrocytic Ca2+‐dependent signalling pathways such as K+ release through BK channels, and the production and release of arachidonic acid metabolites. They are also involved in maintaining the resting tone of the cerebral vessels by releasing ATP and COX‐1 derivatives. Evidence also supports a role for astrocytes in maintaining blood pressure‐dependent change in cerebrovascular tone, and perhaps also in blood vessel‐to‐neuron signalling as posited by the ‘hemo‐neural hypothesis’. Thus, astrocytes are emerging as new stars in preserving the intricate balance between the high energy demand of active neurons and the supply of oxygen and nutrients from the blood by maintaining both resting blood flow and activity‐evoked changes therein. Following neuropathology, astrocytes become reactive and many of their key signalling mechanisms are altered, including those involved in NVC. Furthermore, as they can respond to changes in vascular pressure, cardiovascular diseases might exert previously unknown effects on the central nervous system by altering astrocyte function. This review discusses the role of astrocytes in neurovascular signalling in both physiology and pathology, and the impact of these findings on understanding BOLD‐fMRI signals.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88897846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
F. Romano, A. Tarnutzer, D. Straumann, S. Ramat, G. Bertolini
The cerebellum is the core structure controlling gaze stability. Chronic cerebellar diseases and acute alcohol intoxication affect cerebellar function, inducing, among others, gaze instability as gaze‐evoked nystagmus. Gaze‐evoked nystagmus is characterized by increased centripetal eye‐drift. It is used as an important diagnostic sign for patients with cerebellar degeneration and to assess the ‘driving while intoxicated’ condition. We quantified the effect of alcohol on gaze‐holding using an approach allowing, for the first time, the comparison of deficits induced by alcohol intoxication and cerebellar degeneration. Our results showed that alcohol intoxication induces a two‐fold increase of centripetal eye‐drift. We establish analysis techniques for using controlled alcohol intake as a model to support the study of cerebellar deficits. The observed similarity between the effect of alcohol and the clinical signs observed in cerebellar patients suggests a possible pathomechanism for gaze‐holding deficits.
{"title":"Gaze‐evoked nystagmus induced by alcohol intoxication","authors":"F. Romano, A. Tarnutzer, D. Straumann, S. Ramat, G. Bertolini","doi":"10.1113/JP273204","DOIUrl":"https://doi.org/10.1113/JP273204","url":null,"abstract":"The cerebellum is the core structure controlling gaze stability. Chronic cerebellar diseases and acute alcohol intoxication affect cerebellar function, inducing, among others, gaze instability as gaze‐evoked nystagmus. Gaze‐evoked nystagmus is characterized by increased centripetal eye‐drift. It is used as an important diagnostic sign for patients with cerebellar degeneration and to assess the ‘driving while intoxicated’ condition. We quantified the effect of alcohol on gaze‐holding using an approach allowing, for the first time, the comparison of deficits induced by alcohol intoxication and cerebellar degeneration. Our results showed that alcohol intoxication induces a two‐fold increase of centripetal eye‐drift. We establish analysis techniques for using controlled alcohol intake as a model to support the study of cerebellar deficits. The observed similarity between the effect of alcohol and the clinical signs observed in cerebellar patients suggests a possible pathomechanism for gaze‐holding deficits.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89775407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Lawley, L. Petersen, E. Howden, S. Sarma, W. Cornwell, Rong Zhang, L. Whitworth, Michael A. Williams, B. Levine
Astronauts have recently been discovered to have impaired vision, with a presentation that resembles syndromes of elevated intracranial pressure on Earth. Gravity has a profound effect on fluid distribution and pressure within the human circulation. In contrast to prevailing theory, we observed that microgravity reduces central venous and intracranial pressure. This being said, intracranial pressure is not reduced to the levels observed in the 90 deg seated upright posture on Earth. Thus, over 24 h in zero gravity, pressure in the brain is slightly above that observed on Earth, which may explain remodelling of the eye in astronauts.
{"title":"Effect of gravity and microgravity on intracranial pressure","authors":"J. Lawley, L. Petersen, E. Howden, S. Sarma, W. Cornwell, Rong Zhang, L. Whitworth, Michael A. Williams, B. Levine","doi":"10.1113/JP273557","DOIUrl":"https://doi.org/10.1113/JP273557","url":null,"abstract":"Astronauts have recently been discovered to have impaired vision, with a presentation that resembles syndromes of elevated intracranial pressure on Earth. Gravity has a profound effect on fluid distribution and pressure within the human circulation. In contrast to prevailing theory, we observed that microgravity reduces central venous and intracranial pressure. This being said, intracranial pressure is not reduced to the levels observed in the 90 deg seated upright posture on Earth. Thus, over 24 h in zero gravity, pressure in the brain is slightly above that observed on Earth, which may explain remodelling of the eye in astronauts.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83223563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. D’Amico, A. Butler, M. Héroux, Florence Cotel, J. Perrier, J. Butler, S. Gandevia, Janet L. Taylor
In the adult turtle spinal cord, action potential generation in motoneurones is inhibited by spillover of serotonin to extrasynaptic serotonin 1A (5‐HT1A) receptors at the axon initial segment. We explored whether ingestion of the 5‐HT1A receptor partial agonist, buspirone, decreases motoneurone excitability in humans. Following ingestion of buspirone, two tests of motoneurone excitability showed decreases. F‐wave areas and persistence in an intrinsic muscle of the hand were reduced, as was the area of cervicomedullary motor evoked potentials in biceps brachii. Our findings suggest that activation of 5‐HT1A receptors depresses human motoneurone excitability. Such a depression could contribute to decreased motoneurone output during fatiguing exercise if there is high serotonergic drive to the motoneurones.
{"title":"Human motoneurone excitability is depressed by activation of serotonin 1A receptors with buspirone","authors":"J. D’Amico, A. Butler, M. Héroux, Florence Cotel, J. Perrier, J. Butler, S. Gandevia, Janet L. Taylor","doi":"10.1113/JP273200","DOIUrl":"https://doi.org/10.1113/JP273200","url":null,"abstract":"In the adult turtle spinal cord, action potential generation in motoneurones is inhibited by spillover of serotonin to extrasynaptic serotonin 1A (5‐HT1A) receptors at the axon initial segment. We explored whether ingestion of the 5‐HT1A receptor partial agonist, buspirone, decreases motoneurone excitability in humans. Following ingestion of buspirone, two tests of motoneurone excitability showed decreases. F‐wave areas and persistence in an intrinsic muscle of the hand were reduced, as was the area of cervicomedullary motor evoked potentials in biceps brachii. Our findings suggest that activation of 5‐HT1A receptors depresses human motoneurone excitability. Such a depression could contribute to decreased motoneurone output during fatiguing exercise if there is high serotonergic drive to the motoneurones.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74296143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T. Zou, Daiwen Chen, Qiyuan Yang, Bo Wang, Mei-Jun Zhu, P. Nathanielsz, M. Du
Maternal high‐fat diet impairs brown adipocyte function and correlates with obesity in offspring. Maternal resveratrol administration recovers metabolic activity of offspring brown adipose tissue. Maternal resveratrol promotes beige adipocyte development in offspring white adipose tissue. Maternal resveratrol intervention protects offspring against high‐fat diet‐induced obesity.
{"title":"Resveratrol supplementation of high‐fat diet‐fed pregnant mice promotes brown and beige adipocyte development and prevents obesity in male offspring","authors":"T. Zou, Daiwen Chen, Qiyuan Yang, Bo Wang, Mei-Jun Zhu, P. Nathanielsz, M. Du","doi":"10.1113/JP273478","DOIUrl":"https://doi.org/10.1113/JP273478","url":null,"abstract":"Maternal high‐fat diet impairs brown adipocyte function and correlates with obesity in offspring. Maternal resveratrol administration recovers metabolic activity of offspring brown adipose tissue. Maternal resveratrol promotes beige adipocyte development in offspring white adipose tissue. Maternal resveratrol intervention protects offspring against high‐fat diet‐induced obesity.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86030186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Cruz-Rangel, J. J. Jesús-Pérez, I. Aréchiga-Figueroa, Aldo A. Rodríguez-Menchaca, P. Pérez-Cornejo, H. Hartzell, J. Arreola
The calcium‐activated chloride channel TMEM16A provides a pathway for chloride ion movements that are key in preventing polyspermy, allowing fluid secretion, controlling blood pressure, and enabling gastrointestinal activity. TMEM16A is opened by voltage‐dependent calcium binding and regulated by permeant anions and intracellular protons. Here we show that a low proton concentration reduces TMEM16A activity while maximum activation is obtained when the external proton concentration is high. In addition, protonation conditions determine the open probability of TMEM16A without changing its calcium sensitivity. External glutamic acid 623 (E623) is key for TMEM16A's ability to respond to external protons. At physiological pH, E623 is un‐protonated and TMEM16A is activated when intracellular calcium increases; however, under acidic conditions E623 is partially protonated and works synergistically with intracellular calcium to activate the channel. These findings are critical for understanding physiological and pathological processes that involve changes in pH and chloride flux via TMEM16A.
{"title":"Extracellular protons enable activation of the calcium‐dependent chloride channel TMEM16A","authors":"S. Cruz-Rangel, J. J. Jesús-Pérez, I. Aréchiga-Figueroa, Aldo A. Rodríguez-Menchaca, P. Pérez-Cornejo, H. Hartzell, J. Arreola","doi":"10.1113/JP273111","DOIUrl":"https://doi.org/10.1113/JP273111","url":null,"abstract":"The calcium‐activated chloride channel TMEM16A provides a pathway for chloride ion movements that are key in preventing polyspermy, allowing fluid secretion, controlling blood pressure, and enabling gastrointestinal activity. TMEM16A is opened by voltage‐dependent calcium binding and regulated by permeant anions and intracellular protons. Here we show that a low proton concentration reduces TMEM16A activity while maximum activation is obtained when the external proton concentration is high. In addition, protonation conditions determine the open probability of TMEM16A without changing its calcium sensitivity. External glutamic acid 623 (E623) is key for TMEM16A's ability to respond to external protons. At physiological pH, E623 is un‐protonated and TMEM16A is activated when intracellular calcium increases; however, under acidic conditions E623 is partially protonated and works synergistically with intracellular calcium to activate the channel. These findings are critical for understanding physiological and pathological processes that involve changes in pH and chloride flux via TMEM16A.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90361788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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