Lise Rodat-despoix - Academia.edu (original) (raw)
Papers by Lise Rodat-despoix
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Cancers
In 2018, about 2.1 million women have been diagnosed with breast cancer worldwide. Treatments inc... more In 2018, about 2.1 million women have been diagnosed with breast cancer worldwide. Treatments include—among others—surgery, chemotherapy, radiotherapy, or endocrine therapy. The current policy of care tends rather at therapeutic de-escalation, and systemic treatment such as chemotherapies alone are not systematically considered as the best option anymore. With recent advances in the understanding of cancer biology, and as a complement to anatomic staging, some biological factors (assessed notably via gene-expression signatures) are taken into account to evaluate the benefit of a chemotherapy regimen. The first aim of this review will be to summarize when chemotherapies can be avoided or used only combined with other treatments. The second aim will focus on molecules that can be used instead of chemotherapeutic drugs or used in combination with chemotherapeutic drugs to improve treatment outcomes. These therapeutic molecules have emerged from the collaboration between fundamental and...
Cancers
In the battle against cancer cells, therapeutic modalities are drastically limited by intrinsic o... more In the battle against cancer cells, therapeutic modalities are drastically limited by intrinsic or acquired drug resistance. Resistance to therapy is not only common, but expected: if systemic agents used for cancer treatment are usually active at the beginning of therapy (i.e., 90% of primary breast cancers and 50% of metastases), about 30% of patients with early-stage breast cancer will have recurrent disease. Altered expression of ion channels is now considered as one of the hallmarks of cancer, and several ion channels have been linked to cancer cell resistance. While ion channels have been associated with cell death, apoptosis and even chemoresistance since the late 80s, the molecular mechanisms linking ion channel expression and/or function with chemotherapy have mostly emerged in the last ten years. In this review, we will highlight the relationships between ion channels and resistance to chemotherapy, with a special emphasis on the underlying molecular mechanisms.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Cell death and differentiation, Jan 11, 2018
Orai proteins are highly selective calcium channels playing an important role in calcium entry. O... more Orai proteins are highly selective calcium channels playing an important role in calcium entry. Orai3 channels are overexpressed in breast cancer (BC) tissues, and involved in their proliferation, cell cycle progression and survival. Herein, we sought to address the involvement of Orai3 in resistance to chemotherapeutic drugs. Using high-throughput approaches, we investigated major changes induced by Orai3 overexpression, including downstream signaling mechanisms involved in BC chemotherapy resistance. Resistance was dependent on external calcium presence and thus Orai3 functionality. This effect allowed a downregulation of the p53 tumor suppressor protein expression via the pro-survival PI3K/Sgk-1/Sek-1 pathway. We demonstrated that p53 degradation occurred not only via Mdm2, but also via another unexpected E3 ubiquitin ligase, Nedd4-2. We found supporting bioinformatic evidence linking Orai3 overexpression and chemoresistance in large human BC data sets. Altogether, our results sh...
Oncotarget
Breast cancer remains a research priority due to its invasive phenotype. Although the role of ion... more Breast cancer remains a research priority due to its invasive phenotype. Although the role of ion channels in cancer is now well established, the role of inositol (1,4,5)-trisphosphate (IP 3) receptors (IP 3 Rs) remains enigmatic. If the three IP 3 Rs subtypes expression have been identified in various cancers, little is known about their physiological role. Here, we investigated the involvement of IP 3 R type 3 (IP 3 R 3) in the migration processes of three human breast cancer cell lines showing different migration velocities: the low-migrating MCF-7 and the highly migrating and invasive MDA-MB-231 and MDA-MB-435S cell lines. We show that a higher IP 3 R3 expression level, but not IP 3 R1 nor IP 3 R2, is correlated to a stronger cell line migration capacity and a sustained calcium signal. Interestingly, silencing of IP 3 R3 highlights an oscillating calcium signaling profile and leads to a significant decrease of cell migration capacities of the three breast cancer cell lines. Conversely, stable overexpression of IP 3 R3 in MCF-7 cells significantly increases their migration capacities. This effect is completely reversed by IP 3 R3 silencing. In conclusion, we demonstrate that IP 3 R3 expression level increases the migration capacity of human breast cancer cells by changing the calcium signature.
Biochimica et biophysica acta, Jan 20, 2015
DNA methylation at CpG sites is an epigenetic mechanism that regulates cellular gene expression. ... more DNA methylation at CpG sites is an epigenetic mechanism that regulates cellular gene expression. In cancer cells, aberrant methylation is correlated with the abnormalities in expression of genes that are known to be involved in the particular characteristics of cancer cells such as proliferation, apoptosis, migration or invasion. During the past 30years, accumulating data have definitely convinced the scientific community that ion channels are involved in cancerogenesis and cancer properties. As they are situated at the cell surface, they might be prime targets in the development of new therapeutic strategies besides their potential use as prognostic factors. Despite the progress in our understanding of the remodeling of ion channels in cancer cells, the molecular mechanisms underlying their over- or down-expression remained enigmatic. In this review, we aimed to summarize the available data on gene promoter methylation of ion channels and to investigate their clinical significance ...
Pflügers Archiv - European Journal of Physiology, 2007
5-Hydroxytryptamine (5-HT) is a potent pulmonary vasoconstrictor and mitogenic agent whose concen... more 5-Hydroxytryptamine (5-HT) is a potent pulmonary vasoconstrictor and mitogenic agent whose concentration increases in pulmonary hypertensive patients. Chronic hypoxia induces selective pulmonary arterial hypertension; therefore, we investigated chronic hypoxia effect on the calcium and contractile responses to 5-HT focusing on voltage-independent calcium influx in rat intrapulmonary arteries. Chronic hypoxia, induced by introducing rats in a hypobaric chamber for 3 weeks, potentiated the contraction to 5-HT and this effect was insensitive to nitrendipine. Calcium signal to 5-HT was characterized by a transient followed by a sustained phase in both normoxia and chronic hypoxia. The sustained phase was dependent on extracellular calcium and inhibited by lanthanum. RHC 80267, a specific inhibitor of diacylglycerol lipase, reduced the 5-HT-induced calcium influx in chronic hypoxia but not in normoxia. Furthermore, unlike gadolinium, RHC 80267 inhibited more the contraction to 5-HT in chronic hypoxia. Despite the apparent role of voltage-independent calcium channels in chronic hypoxia, Western blot and flow cytometry analyses demonstrated no variations in TRPC 6 expression. This study shows for the first time that the 5-HT-induced calcium and contractile signals in chronic hypoxia are more dependent on a voltage-independent, RHC 80267sensitive calcium influx and the hyperreactivity to 5-HT may thus be explained by this influx.
Journal of Biological Chemistry, 2011
Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited cause of kidney f... more Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited cause of kidney failure, is caused by mutations in either PKD1 (85%) or PKD2 (15%). The PKD2 protein, polycystin-2 (PC2 or TRPP2), is a member of the transient receptor potential (TRP) superfamily and functions as a nonselective calcium channel. PC2 has been found to form oligomers in native tissues, suggesting that similar to other TRP channels, it may form functional homo-or heterotetramers with other TRP subunits. We have recently demonstrated that the homodimerization of PC2 is mediated by both N-terminal and C-terminal domains, and it is known that PC2 can heterodimerize with PC1, TRPC1, and TRPV4. In this paper, we report that a single cysteine residue, Cys 632 , mutated in a known PKD2 pedigree, constitutes the third dimerization domain for PC2. PC2 truncation mutants lacking both N and C termini could still dimerize under nonreducing conditions. Mutation of Cys 632 alone abolished dimerization in these mutants, indicating that it was the critical residue mediating disulfide bond formation between PC2 monomers. Co-expression of C632A PC2 mutants with wild-type PC2 channels reduced ATP-sensitive endoplasmic reticulum Ca 2؉ release in HEK293 cells. The combination of C632A and mutations disrupting the C-terminal coiled-coil domain (Val 846 , Ile 853 , Ile 860 , Leu 867 or 4M) nearly abolished dimer formation and ATP-dependent Ca 2؉ release. However, unlike the 4M PC2 mutant, a C632A mutant could still heterodimerize with polycystin-1 (PC1). Our results indicate that PC2 homodimerization is regulated by three distinct domains and that these events regulate formation of the tetrameric PC2 channel.
European Journal of Cancer, 2013
Breast cancer Proliferation Type 3 inositol 1,4,5-trisphosphate receptor voltage-and Ca 2+-depend... more Breast cancer Proliferation Type 3 inositol 1,4,5-trisphosphate receptor voltage-and Ca 2+-dependent K + channels BK Ca channel Ca 2+
Nature Reviews …, 2011
A sensory receptor that responds to mechanical pressure or distortion by causing membrane depolar... more A sensory receptor that responds to mechanical pressure or distortion by causing membrane depolarization and action potential firing. Mechanotransducer channel An ion channel present in the cell membranes of prokaryotes and eukaryotes, capable of generating an ion flux signal as a response to mechanical stimuli.
Mechanosensitivity of the Nervous System, 2009
... Alessandri-Haber N, Joseph E, Dina OA, Liedtke W, Levine JD (2005) TRPV4 mediates pain-relate... more ... Alessandri-Haber N, Joseph E, Dina OA, Liedtke W, Levine JD (2005) TRPV4 mediates pain-related behavior induced by mild hypertonic stimuli in the ... Garcıa-Anoveros J, Samad TA, Zuvela-Jelaska L, Woolf CJ, Corey DP (2001) Transport and localization of the DEG/ENaC ion ...
European Respiratory Journal, 2009
Serotonin (5-hydroxytryptamine; 5-HT) is a potent pulmonary vasoconstrictor and mitogenic agent w... more Serotonin (5-hydroxytryptamine; 5-HT) is a potent pulmonary vasoconstrictor and mitogenic agent whose plasma level is increased in pulmonary hypertensive patients. Thus, we explored the signalling pathways involved in the contractile response to 5-HT in human pulmonary arteries (HPAs).
A. Smith. Regulation in organotypic cultures of dorsal root ganglia (DRG) from of N-and L-type Ca... more A. Smith. Regulation in organotypic cultures of dorsal root ganglia (DRG) from of N-and L-type Ca 2/ channels in adult frog sympathetic ganglion 13 d fetal mice. They proposed that this effect may reflect B cells by nerve growth factor in vitro and in vivo. J. Neurophysiol. modulation of Ca 2/ channel current (I Ca ) in neurons that no 78: 3359-3370, 1997. To examine mechanisms responsible for the longer require NGF for survival. By contrast, Ritter and long-term regulation of Ca 2/ -channels in an adult neuron, changes showed that treatment of neonatal rats with in whole cell Ba 2/ current (I Ba ) were examined in adult bullfrog NGF in vivo from birth to 5 wk of age produced essentially sympathetic ganglion B cells in vitro. Cells were cultured at low the reverse effect; ap duration was increased. This effect density in defined, serum free medium. After 15 days, total I Ba was was confined to high-threshold mechanoreceptor (HTMR) similar to the initial value, whereas I Ba density was reduced by neurons and other types of sensory neuron were unaffected.
Cell reports, Jan 19, 2015
Cold-triggered pain is essential to avoid prolonged exposure to harmfully low temperatures. Howev... more Cold-triggered pain is essential to avoid prolonged exposure to harmfully low temperatures. However, the molecular basis of noxious cold sensing in mammals is still not completely understood. Here, we show that the voltage-gated Nav1.9 sodium channel is important for the perception of pain in response to noxious cold. Nav1.9 activity is upregulated in a subpopulation of damage-sensing sensory neurons responding to cooling, which allows the channel to amplify subthreshold depolarizations generated by the activation of cold transducers. Consequently, cold-triggered firing is impaired in Nav1.9(-/-) neurons, and Nav1.9 null mice and knockdown rats show increased cold pain thresholds. Disrupting Nav1.9 expression in rodents also alleviates cold pain hypersensitivity induced by the antineoplastic agent oxaliplatin. We conclude that Nav1.9 acts as a subthreshold amplifier in cold-sensitive nociceptive neurons and is required for the perception of cold pain under normal and pathological co...
Sensors, 2007
Mechanoreceptive sensory neurons innervating the skin, skeletal muscles and viscera signal both i... more Mechanoreceptive sensory neurons innervating the skin, skeletal muscles and viscera signal both innocuous and noxious information necessary for proprioception, touch and pain. These neurons are responsible for the transduction of mechanical stimuli into action potentials that propagate to the central nervous system. The ability of these cells to detect mechanical stimuli impinging on them relies on the presence of mechanosensitive channels that transduce the external mechanical forces into electrical and chemical signals. Although a great deal of information regarding the molecular and biophysical properties of mechanosensitive channels in prokaryotes has been accumulated over the past two decades, less is known about the mechanosensitive channels necessary for proprioception and the senses of touch and pain. This review summarizes the most pertinent data on mechanosensitive channels of mammalian somatosensory neurons, focusing on their properties, pharmacology and putative identity.
The EMBO Journal, 2010
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in two genes, PKD1 an... more Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in two genes, PKD1 and PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Earlier work has shown that PC1 and PC2 assemble into a polycystin complex implicated in kidney morphogenesis. PC2 also assembles into homomers of uncertain functional significance. However, little is known about the molecular mechanisms that direct polycystin complex assembly and specify its functions. We have identified a coiled coil in the C-terminus of PC2 that functions as a homodimerization domain essential for PC1 binding but not for its self-oligomerization. Dimerization-defective PC2 mutants were unable to reconstitute PC1/PC2 complexes either at the plasma membrane (PM) or at PM-endoplasmic reticulum (ER) junctions but could still function as ER Ca 2 þ -release channels. Expression of dimerization-defective PC2 mutants in zebrafish resulted in a cystic phenotype but had lesser effects on organ laterality. We conclude that C-terminal dimerization of PC2 specifies the formation of polycystin complexes but not formation of ER-localized PC2 channels. Mutations that affect PC2 C-terminal homo-and heteromerization are the likely molecular basis of cyst formation in ADPKD.
Pflügers Archiv - European Journal of Physiology, 2009
The primary cilium is a microtubule-based nonmotile organelle that is found on most cells in the ... more The primary cilium is a microtubule-based nonmotile organelle that is found on most cells in the mammalian body. Once regarded as a vestigial organelle, it has been recently shown to play unforeseen roles in mammalian physiology and tissue homeostasis. In kidney epithelial cells, the primary cilium plays a fundamental role in tubule organization and function and it is now considered to serve as a versatile mechanosensor and chemosensor. Diseases related to kidney primary cilia include autosomal polycystic kidney disease, recessive polycystic kidney disease, Bardet-Biedl syndrome, and nephronophthisis. Multiple proteins whose functions are disrupted in cystic kidney diseases have been localized in the primary cilium. This review provides a general introduction to the cell biology and function of renal primary cilia and an overview of cilia-related kidney diseases.
Nature Reviews Neuroscience, 2011
The somatosensory system mediates fundamental physiological functions, including the senses of to... more The somatosensory system mediates fundamental physiological functions, including the senses of touch, pain and proprioception. This variety of functions is matched by a diverse array of mechanosensory neurons that respond to force in a specific fashion. Mechanotransduction begins at the sensory nerve endings, which rapidly transform mechanical forces into electrical signals. Progress has been made in establishing the functional properties of mechanoreceptors, but it has been remarkably difficult to characterize mechanotranducer channels at the molecular level. However, in the past few years, new functional assays have provided insights into the basic properties and molecular identity of mechanotransducer channels in mammalian sensory neurons. The recent identification of novel families of proteins as mechanosensing molecules will undoubtedly accelerate our understanding of mechanotransduction mechanisms in mammalian somatosensation.
The Journal of General Physiology, 2008
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Cancers
In 2018, about 2.1 million women have been diagnosed with breast cancer worldwide. Treatments inc... more In 2018, about 2.1 million women have been diagnosed with breast cancer worldwide. Treatments include—among others—surgery, chemotherapy, radiotherapy, or endocrine therapy. The current policy of care tends rather at therapeutic de-escalation, and systemic treatment such as chemotherapies alone are not systematically considered as the best option anymore. With recent advances in the understanding of cancer biology, and as a complement to anatomic staging, some biological factors (assessed notably via gene-expression signatures) are taken into account to evaluate the benefit of a chemotherapy regimen. The first aim of this review will be to summarize when chemotherapies can be avoided or used only combined with other treatments. The second aim will focus on molecules that can be used instead of chemotherapeutic drugs or used in combination with chemotherapeutic drugs to improve treatment outcomes. These therapeutic molecules have emerged from the collaboration between fundamental and...
Cancers
In the battle against cancer cells, therapeutic modalities are drastically limited by intrinsic o... more In the battle against cancer cells, therapeutic modalities are drastically limited by intrinsic or acquired drug resistance. Resistance to therapy is not only common, but expected: if systemic agents used for cancer treatment are usually active at the beginning of therapy (i.e., 90% of primary breast cancers and 50% of metastases), about 30% of patients with early-stage breast cancer will have recurrent disease. Altered expression of ion channels is now considered as one of the hallmarks of cancer, and several ion channels have been linked to cancer cell resistance. While ion channels have been associated with cell death, apoptosis and even chemoresistance since the late 80s, the molecular mechanisms linking ion channel expression and/or function with chemotherapy have mostly emerged in the last ten years. In this review, we will highlight the relationships between ion channels and resistance to chemotherapy, with a special emphasis on the underlying molecular mechanisms.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Cell death and differentiation, Jan 11, 2018
Orai proteins are highly selective calcium channels playing an important role in calcium entry. O... more Orai proteins are highly selective calcium channels playing an important role in calcium entry. Orai3 channels are overexpressed in breast cancer (BC) tissues, and involved in their proliferation, cell cycle progression and survival. Herein, we sought to address the involvement of Orai3 in resistance to chemotherapeutic drugs. Using high-throughput approaches, we investigated major changes induced by Orai3 overexpression, including downstream signaling mechanisms involved in BC chemotherapy resistance. Resistance was dependent on external calcium presence and thus Orai3 functionality. This effect allowed a downregulation of the p53 tumor suppressor protein expression via the pro-survival PI3K/Sgk-1/Sek-1 pathway. We demonstrated that p53 degradation occurred not only via Mdm2, but also via another unexpected E3 ubiquitin ligase, Nedd4-2. We found supporting bioinformatic evidence linking Orai3 overexpression and chemoresistance in large human BC data sets. Altogether, our results sh...
Oncotarget
Breast cancer remains a research priority due to its invasive phenotype. Although the role of ion... more Breast cancer remains a research priority due to its invasive phenotype. Although the role of ion channels in cancer is now well established, the role of inositol (1,4,5)-trisphosphate (IP 3) receptors (IP 3 Rs) remains enigmatic. If the three IP 3 Rs subtypes expression have been identified in various cancers, little is known about their physiological role. Here, we investigated the involvement of IP 3 R type 3 (IP 3 R 3) in the migration processes of three human breast cancer cell lines showing different migration velocities: the low-migrating MCF-7 and the highly migrating and invasive MDA-MB-231 and MDA-MB-435S cell lines. We show that a higher IP 3 R3 expression level, but not IP 3 R1 nor IP 3 R2, is correlated to a stronger cell line migration capacity and a sustained calcium signal. Interestingly, silencing of IP 3 R3 highlights an oscillating calcium signaling profile and leads to a significant decrease of cell migration capacities of the three breast cancer cell lines. Conversely, stable overexpression of IP 3 R3 in MCF-7 cells significantly increases their migration capacities. This effect is completely reversed by IP 3 R3 silencing. In conclusion, we demonstrate that IP 3 R3 expression level increases the migration capacity of human breast cancer cells by changing the calcium signature.
Biochimica et biophysica acta, Jan 20, 2015
DNA methylation at CpG sites is an epigenetic mechanism that regulates cellular gene expression. ... more DNA methylation at CpG sites is an epigenetic mechanism that regulates cellular gene expression. In cancer cells, aberrant methylation is correlated with the abnormalities in expression of genes that are known to be involved in the particular characteristics of cancer cells such as proliferation, apoptosis, migration or invasion. During the past 30years, accumulating data have definitely convinced the scientific community that ion channels are involved in cancerogenesis and cancer properties. As they are situated at the cell surface, they might be prime targets in the development of new therapeutic strategies besides their potential use as prognostic factors. Despite the progress in our understanding of the remodeling of ion channels in cancer cells, the molecular mechanisms underlying their over- or down-expression remained enigmatic. In this review, we aimed to summarize the available data on gene promoter methylation of ion channels and to investigate their clinical significance ...
Pflügers Archiv - European Journal of Physiology, 2007
5-Hydroxytryptamine (5-HT) is a potent pulmonary vasoconstrictor and mitogenic agent whose concen... more 5-Hydroxytryptamine (5-HT) is a potent pulmonary vasoconstrictor and mitogenic agent whose concentration increases in pulmonary hypertensive patients. Chronic hypoxia induces selective pulmonary arterial hypertension; therefore, we investigated chronic hypoxia effect on the calcium and contractile responses to 5-HT focusing on voltage-independent calcium influx in rat intrapulmonary arteries. Chronic hypoxia, induced by introducing rats in a hypobaric chamber for 3 weeks, potentiated the contraction to 5-HT and this effect was insensitive to nitrendipine. Calcium signal to 5-HT was characterized by a transient followed by a sustained phase in both normoxia and chronic hypoxia. The sustained phase was dependent on extracellular calcium and inhibited by lanthanum. RHC 80267, a specific inhibitor of diacylglycerol lipase, reduced the 5-HT-induced calcium influx in chronic hypoxia but not in normoxia. Furthermore, unlike gadolinium, RHC 80267 inhibited more the contraction to 5-HT in chronic hypoxia. Despite the apparent role of voltage-independent calcium channels in chronic hypoxia, Western blot and flow cytometry analyses demonstrated no variations in TRPC 6 expression. This study shows for the first time that the 5-HT-induced calcium and contractile signals in chronic hypoxia are more dependent on a voltage-independent, RHC 80267sensitive calcium influx and the hyperreactivity to 5-HT may thus be explained by this influx.
Journal of Biological Chemistry, 2011
Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited cause of kidney f... more Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited cause of kidney failure, is caused by mutations in either PKD1 (85%) or PKD2 (15%). The PKD2 protein, polycystin-2 (PC2 or TRPP2), is a member of the transient receptor potential (TRP) superfamily and functions as a nonselective calcium channel. PC2 has been found to form oligomers in native tissues, suggesting that similar to other TRP channels, it may form functional homo-or heterotetramers with other TRP subunits. We have recently demonstrated that the homodimerization of PC2 is mediated by both N-terminal and C-terminal domains, and it is known that PC2 can heterodimerize with PC1, TRPC1, and TRPV4. In this paper, we report that a single cysteine residue, Cys 632 , mutated in a known PKD2 pedigree, constitutes the third dimerization domain for PC2. PC2 truncation mutants lacking both N and C termini could still dimerize under nonreducing conditions. Mutation of Cys 632 alone abolished dimerization in these mutants, indicating that it was the critical residue mediating disulfide bond formation between PC2 monomers. Co-expression of C632A PC2 mutants with wild-type PC2 channels reduced ATP-sensitive endoplasmic reticulum Ca 2؉ release in HEK293 cells. The combination of C632A and mutations disrupting the C-terminal coiled-coil domain (Val 846 , Ile 853 , Ile 860 , Leu 867 or 4M) nearly abolished dimer formation and ATP-dependent Ca 2؉ release. However, unlike the 4M PC2 mutant, a C632A mutant could still heterodimerize with polycystin-1 (PC1). Our results indicate that PC2 homodimerization is regulated by three distinct domains and that these events regulate formation of the tetrameric PC2 channel.
European Journal of Cancer, 2013
Breast cancer Proliferation Type 3 inositol 1,4,5-trisphosphate receptor voltage-and Ca 2+-depend... more Breast cancer Proliferation Type 3 inositol 1,4,5-trisphosphate receptor voltage-and Ca 2+-dependent K + channels BK Ca channel Ca 2+
Nature Reviews …, 2011
A sensory receptor that responds to mechanical pressure or distortion by causing membrane depolar... more A sensory receptor that responds to mechanical pressure or distortion by causing membrane depolarization and action potential firing. Mechanotransducer channel An ion channel present in the cell membranes of prokaryotes and eukaryotes, capable of generating an ion flux signal as a response to mechanical stimuli.
Mechanosensitivity of the Nervous System, 2009
... Alessandri-Haber N, Joseph E, Dina OA, Liedtke W, Levine JD (2005) TRPV4 mediates pain-relate... more ... Alessandri-Haber N, Joseph E, Dina OA, Liedtke W, Levine JD (2005) TRPV4 mediates pain-related behavior induced by mild hypertonic stimuli in the ... Garcıa-Anoveros J, Samad TA, Zuvela-Jelaska L, Woolf CJ, Corey DP (2001) Transport and localization of the DEG/ENaC ion ...
European Respiratory Journal, 2009
Serotonin (5-hydroxytryptamine; 5-HT) is a potent pulmonary vasoconstrictor and mitogenic agent w... more Serotonin (5-hydroxytryptamine; 5-HT) is a potent pulmonary vasoconstrictor and mitogenic agent whose plasma level is increased in pulmonary hypertensive patients. Thus, we explored the signalling pathways involved in the contractile response to 5-HT in human pulmonary arteries (HPAs).
A. Smith. Regulation in organotypic cultures of dorsal root ganglia (DRG) from of N-and L-type Ca... more A. Smith. Regulation in organotypic cultures of dorsal root ganglia (DRG) from of N-and L-type Ca 2/ channels in adult frog sympathetic ganglion 13 d fetal mice. They proposed that this effect may reflect B cells by nerve growth factor in vitro and in vivo. J. Neurophysiol. modulation of Ca 2/ channel current (I Ca ) in neurons that no 78: 3359-3370, 1997. To examine mechanisms responsible for the longer require NGF for survival. By contrast, Ritter and long-term regulation of Ca 2/ -channels in an adult neuron, changes showed that treatment of neonatal rats with in whole cell Ba 2/ current (I Ba ) were examined in adult bullfrog NGF in vivo from birth to 5 wk of age produced essentially sympathetic ganglion B cells in vitro. Cells were cultured at low the reverse effect; ap duration was increased. This effect density in defined, serum free medium. After 15 days, total I Ba was was confined to high-threshold mechanoreceptor (HTMR) similar to the initial value, whereas I Ba density was reduced by neurons and other types of sensory neuron were unaffected.
Cell reports, Jan 19, 2015
Cold-triggered pain is essential to avoid prolonged exposure to harmfully low temperatures. Howev... more Cold-triggered pain is essential to avoid prolonged exposure to harmfully low temperatures. However, the molecular basis of noxious cold sensing in mammals is still not completely understood. Here, we show that the voltage-gated Nav1.9 sodium channel is important for the perception of pain in response to noxious cold. Nav1.9 activity is upregulated in a subpopulation of damage-sensing sensory neurons responding to cooling, which allows the channel to amplify subthreshold depolarizations generated by the activation of cold transducers. Consequently, cold-triggered firing is impaired in Nav1.9(-/-) neurons, and Nav1.9 null mice and knockdown rats show increased cold pain thresholds. Disrupting Nav1.9 expression in rodents also alleviates cold pain hypersensitivity induced by the antineoplastic agent oxaliplatin. We conclude that Nav1.9 acts as a subthreshold amplifier in cold-sensitive nociceptive neurons and is required for the perception of cold pain under normal and pathological co...
Sensors, 2007
Mechanoreceptive sensory neurons innervating the skin, skeletal muscles and viscera signal both i... more Mechanoreceptive sensory neurons innervating the skin, skeletal muscles and viscera signal both innocuous and noxious information necessary for proprioception, touch and pain. These neurons are responsible for the transduction of mechanical stimuli into action potentials that propagate to the central nervous system. The ability of these cells to detect mechanical stimuli impinging on them relies on the presence of mechanosensitive channels that transduce the external mechanical forces into electrical and chemical signals. Although a great deal of information regarding the molecular and biophysical properties of mechanosensitive channels in prokaryotes has been accumulated over the past two decades, less is known about the mechanosensitive channels necessary for proprioception and the senses of touch and pain. This review summarizes the most pertinent data on mechanosensitive channels of mammalian somatosensory neurons, focusing on their properties, pharmacology and putative identity.
The EMBO Journal, 2010
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in two genes, PKD1 an... more Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in two genes, PKD1 and PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Earlier work has shown that PC1 and PC2 assemble into a polycystin complex implicated in kidney morphogenesis. PC2 also assembles into homomers of uncertain functional significance. However, little is known about the molecular mechanisms that direct polycystin complex assembly and specify its functions. We have identified a coiled coil in the C-terminus of PC2 that functions as a homodimerization domain essential for PC1 binding but not for its self-oligomerization. Dimerization-defective PC2 mutants were unable to reconstitute PC1/PC2 complexes either at the plasma membrane (PM) or at PM-endoplasmic reticulum (ER) junctions but could still function as ER Ca 2 þ -release channels. Expression of dimerization-defective PC2 mutants in zebrafish resulted in a cystic phenotype but had lesser effects on organ laterality. We conclude that C-terminal dimerization of PC2 specifies the formation of polycystin complexes but not formation of ER-localized PC2 channels. Mutations that affect PC2 C-terminal homo-and heteromerization are the likely molecular basis of cyst formation in ADPKD.
Pflügers Archiv - European Journal of Physiology, 2009
The primary cilium is a microtubule-based nonmotile organelle that is found on most cells in the ... more The primary cilium is a microtubule-based nonmotile organelle that is found on most cells in the mammalian body. Once regarded as a vestigial organelle, it has been recently shown to play unforeseen roles in mammalian physiology and tissue homeostasis. In kidney epithelial cells, the primary cilium plays a fundamental role in tubule organization and function and it is now considered to serve as a versatile mechanosensor and chemosensor. Diseases related to kidney primary cilia include autosomal polycystic kidney disease, recessive polycystic kidney disease, Bardet-Biedl syndrome, and nephronophthisis. Multiple proteins whose functions are disrupted in cystic kidney diseases have been localized in the primary cilium. This review provides a general introduction to the cell biology and function of renal primary cilia and an overview of cilia-related kidney diseases.
Nature Reviews Neuroscience, 2011
The somatosensory system mediates fundamental physiological functions, including the senses of to... more The somatosensory system mediates fundamental physiological functions, including the senses of touch, pain and proprioception. This variety of functions is matched by a diverse array of mechanosensory neurons that respond to force in a specific fashion. Mechanotransduction begins at the sensory nerve endings, which rapidly transform mechanical forces into electrical signals. Progress has been made in establishing the functional properties of mechanoreceptors, but it has been remarkably difficult to characterize mechanotranducer channels at the molecular level. However, in the past few years, new functional assays have provided insights into the basic properties and molecular identity of mechanotransducer channels in mammalian sensory neurons. The recent identification of novel families of proteins as mechanosensing molecules will undoubtedly accelerate our understanding of mechanotransduction mechanisms in mammalian somatosensation.
The Journal of General Physiology, 2008