Publications by authors named "Lise Rodat-Despoix"

18 Publications

  • Page 1 of 1

Beyond Chemotherapies: Recent Strategies in Breast Cancer Treatment.

Cancers (Basel) 2020 Sep 16;12(9). Epub 2020 Sep 16.

Laboratoire de Physiologie Cellulaire et Moléculaire (UR-UPJV 4667), UFR des Sciences, Université de Picardie Jules Verne, 33 Rue St Leu, 80039 Amiens, France.

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 clinical research, and include molecules, such as tyrosine kinase inhibitors, CDK4/6 inhibitors, and monoclonal antibodies (such as anti-PD-L1). In the fight against cancer, new tools aiding decision making are of the utmost importance: gene-expression signatures have proven to be valuable in the clinic, notably, to know when chemotherapies can be avoided. When substitution treatments are also available, a big step can be made toward personalized medicine for the patient's benefit.
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http://dx.doi.org/10.3390/cancers12092634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565588PMC
September 2020

Ion Channels: New Actors Playing in Chemotherapeutic Resistance.

Cancers (Basel) 2019 Mar 16;11(3). Epub 2019 Mar 16.

Laboratoire de Physiologie Cellulaire et Moléculaire (EA 4667), Université de Picardie Jules Verne, UFR des Sciences, 33 Rue St Leu, 80039 Amiens, France.

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.
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http://dx.doi.org/10.3390/cancers11030376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468599PMC
March 2019

IPR3 silencing induced actin cytoskeletal reorganization through ARHGAP18/RhoA/mDia1/FAK pathway in breast cancer cell lines.

Biochim Biophys Acta Mol Cell Res 2018 07 7;1865(7):945-958. Epub 2018 Apr 7.

LPCM, Laboratoire de Physiologie Cellulaire et Moléculaire, EA-4667: "Canaux ioniques dans le cancer du sein"; Université de Picardie Jules Verne, 33 Rue Saint-Leu, 80039 Amiens Cedex, France. Electronic address:

Cell morphology is altered in the migration process, and the underlying cytoskeleton remodeling is highly dependent of intracellular Ca concentration. Many calcium channels are known to be involved in migration. Inositol 1,4,5-trisphosphate receptor (IPR) was demonstrated to be implicated in breast cancer cells migration, but its involvement in morphological changes during the migration process remains unclear. In the present work, we showed that IPR3 expression was correlated to cell morphology. IPR3 silencing induced rounding shape and decreased adhesion in invasive breast cancer cell lines. Moreover, IPR3 silencing decreased ARHGAP18 expression, RhoA activity, Cdc42 expression and FAK phosphorylation. Interestingly, IPR3 was able to regulate profilin remodeling, without inducing any myosin II reorganization. IPR3 silencing revealed an oscillatory calcium signature, with a predominant oscillating profile occurring in early wound repair. To summarize, we demonstrated that IPR3 is able to modulate intracellular Ca availability and to coordinate the remodeling of profilin cytoskeleton organization through the ARHGAP18/RhoA/mDia1/FAK pathway.
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http://dx.doi.org/10.1016/j.bbamcr.2018.04.002DOI Listing
July 2018

Orai3 calcium channel and resistance to chemotherapy in breast cancer cells: the p53 connection.

Cell Death Differ 2018 03 11;25(4):693-707. Epub 2018 Jan 11.

Université de Picardie Jules Verne, UFR des Sciences, Laboratoire de Physiologie Cellulaire et Moléculaire (EA 4667), SFR CAP-SANTE (FED 4231), Amiens, France.

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 shed light on the molecular mechanisms activated in BC cells commonly found to overexpress Orai3, allowing resistance to chemotherapeutic drugs.
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http://dx.doi.org/10.1038/s41418-017-0007-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864197PMC
March 2018

Downregulation of type 3 inositol (1,4,5)-trisphosphate receptor decreases breast cancer cell migration through an oscillatory Ca signal.

Oncotarget 2017 Sep 18;8(42):72324-72341. Epub 2017 Aug 18.

Laboratory of Cellular and Molecular Physiology (EA-4667), "Ion Channels in Breast Cancer", SFR CAP-SANTE (FED-4231), University of Amiens, UFR Sciences, 80039 Amiens, France.

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) receptors (IPRs) remains enigmatic. If the three IPRs subtypes expression have been identified in various cancers, little is known about their physiological role. Here, we investigated the involvement of IPR type 3 (IPR) 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 IPR3 expression level, but not IPR1 nor IPR2, is correlated to a stronger cell line migration capacity and a sustained calcium signal. Interestingly, silencing of IPR3 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 IPR3 in MCF-7 cells significantly increases their migration capacities. This effect is completely reversed by IPR3 silencing. In conclusion, we demonstrate that IPR3 expression level increases the migration capacity of human breast cancer cells by changing the calcium signature.
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http://dx.doi.org/10.18632/oncotarget.20327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641133PMC
September 2017

The Nav1.9 channel is a key determinant of cold pain sensation and cold allodynia.

Cell Rep 2015 May 7;11(7):1067-78. Epub 2015 May 7.

Pharmacologie Fondamentale et Clinique de la Douleur, Clermont Université, Université d'Auvergne, 63000 Clermont-Ferrand, France; Inserm, U 1107, Neuro-Dol, 63000 Clermont-Ferrand, France. Electronic address:

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 conditions.
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http://dx.doi.org/10.1016/j.celrep.2015.04.027DOI Listing
May 2015

DNA methylation of channel-related genes in cancers.

Biochim Biophys Acta 2015 Oct 20;1848(10 Pt B):2621-8. Epub 2015 Feb 20.

UFR Sciences, EA 4667, Laboratory of Cell and Molecular Physiology, University of Picardie Jules Verne, SFR CAP-SANTE (FED 4231), Amiens, France; Department of Biology, Faculty of Sciences, Ibn Zohr University, Agadir Morocco.

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 30 years, 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 as novel biomarkers in cancer. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
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http://dx.doi.org/10.1016/j.bbamem.2015.02.015DOI Listing
October 2015

Molecular interaction and functional coupling between type 3 inositol 1,4,5-trisphosphate receptor and BKCa channel stimulate breast cancer cell proliferation.

Eur J Cancer 2013 Nov 27;49(17):3738-51. Epub 2013 Aug 27.

Laboratory of Cellular and Molecular Physiology (EA-4667), 'Ion Channels in Breast Cancer', SFR CAP-SANTE (FED-4231), University of Amiens, UFR Sciences, 33 Rue Saint-Leu, 80039 Amiens, France.

Background: The implication of ion channels and inositol 1,4,5-trisphosphate (IP3)-induced Ca(2+) signalling (IICS) in the carcinogenesis processes, including deregulation of cell proliferation, migration and invasion, is increasingly studied. Studies from our laboratory have shown that type 3 IP3 receptor (IP3R3) and voltage- and Ca(2+)-dependent K(+) channels BKCa channels are involved in human breast cancer cell proliferation. In this context, we investigated the probable interaction between these two proteins (IP3R3 and BKCa channel) in normal and in breast cancer cells.

Methods: MCF-7 and MCF-10A cell viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-assay in the presence or absence of adenosine triphosphate (ATP). Furthermore, cell-cycle analysis was carried out and cell cycle protein expression was examined by Western blotting. Immunocytochemistry and co-immunoprecipitation assays were used to check co-localisation of BKCa and IP3R3 and their molecular interaction. Finally, whole cell patch-clamp and Ca(2+) imaging were performed to assess the functional interaction.

Results: Our results are in favour of a functional and a molecular coupling between IP3R3 and BKCa channel that is involved in MCF-7 proliferation. Indeed, ATP increased MCF-7 cell proliferation and this effect was impaired when the expression of BKCa and/or IP3R3 has been reduced by specific small interfering RNAs (siRNAs). Flow cytometry experiments showed that both siRNAs led to cell cycle arrest in the G0/G1 phase and these results were confirmed by the analysis of cell cycle protein expression. Specifically, BKCa and IP3R3 silencing decreased both cyclin-D1 and cyclin-dependent kinase 4 (CDK4) expression levels. Furthermore, ATP elicited a phospholipase C (PLC)-dependent elevation of internal Ca(2+) that triggered in turn an iberiotoxin (IbTx)- and a tetra-ethyl-ammonium (TEA)-sensitive membrane hyperpolarisation that was strongly reduced in the cells with silenced IP3R3 or BKCa. In the same way, intracellular application of Ins(2,4,5)P3 triggered an IbTx-sensitive membrane hyperpolarisation. Moreover, intracellular Ca(2+) chelation with 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) prevented ATP-induced BKCa activation. BKCa and IP3R3 also co-immunoprecipitated and this interaction seemed to occur in cholesterol-enriched microdomains. Conversely, in the normal breast cell line MCF-10A, neither ATP application nor BKCa silencing affected cell proliferation. Furthermore, IP3R3 and BKCa did not co-immunoprecipitate, suggesting the absence of a molecular coupling between BKCa and IP3R3 in the MCF-10A normal cell line.

Conclusion: Altogether, our results suggest a molecular and functional link between BKCa channel and IP3R3 in cancer cells. Our findings led us to propose this coupling between BKCa and IP3R3 as an important mechanism for tumour cell proliferation.
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http://dx.doi.org/10.1016/j.ejca.2013.07.013DOI Listing
November 2013

Shear stress-induced Ca²⁺ mobilization in MDCK cells is ATP dependent, no matter the primary cilium.

Cell Calcium 2013 May-Jun;53(5-6):327-37. Epub 2013 Mar 23.

Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, UMR 7286, CNRS, Université AIX-MARSEILLE, CS80011 Bd Pierre Dramard, 13344 Marseille Cedex 15, France.

Primary cilium has emerged as mechanosensor to subtle flow variations in epithelial cells, but its role in shear stress detection remains controversial. To probe the function of this non-motile organelle in shear stress detection by cells, we compared calcium signalling responses induced by shear stress in ciliated and unciliated MDCK cells. Cytosolic free Ca²⁺ ([Ca²⁺]i) was measured using Fura-PE3 video imaging fluorescence microscopy in response to shear stress due to laminar flow (385 μl s⁻¹). Our results show that both unciliated and ciliated MDCK cells are shear stress sensitive via ATP release and autocrine feedback through purinergic receptors. However, purinergic calcium signals differed in response intensity and receptor subtypes. In unciliated cells, shear stress-induced elevation in [Ca²⁺]i was predominantly mediated through P2X receptors (P2XR). In contrast, calcium mobilization in ciliated MDCK cells resulted from P2YRs and store-operated Ca²⁺-permeable channels besides P2XRs. These findings lend support to the hypothesis that ATP release in response to shear stress is independent of the primary cilium and that transduction of mechanical strain into a specific biochemical responses stems on the mobilization of different sets of purinergic receptors.
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http://dx.doi.org/10.1016/j.ceca.2013.02.002DOI Listing
December 2013

A single amino acid residue constitutes the third dimerization domain essential for the assembly and function of the tetrameric polycystin-2 (TRPP2) channel.

J Biol Chem 2011 May 7;286(21):18994-9000. Epub 2011 Apr 7.

Kidney Genetics Group, Academic Unit of Nephrology, The Henry Wellcome Laboratories for Medical Research, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, United Kingdom.

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.
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http://dx.doi.org/10.1074/jbc.M110.192286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3099714PMC
May 2011

ATP signalling is crucial for the response of human keratinocytes to mechanical stimulation by hypo-osmotic shock.

Exp Dermatol 2011 May 28;20(5):401-7. Epub 2011 Feb 28.

Université de la Méditerranée, Centre National de la Recherche Scientifique (CNRS) UMR6231, Marseille, France.

Touch is detected through receptors located in the skin and the activation of channels in sensory nerve fibres. Epidermal keratinocytes themselves, however, may sense mechanical stimulus and contribute to skin sensation. Here, we showed that the mechanical stimulation of human keratinocytes by hypo-osmotic shock releases adenosine triphosphate (ATP) and increases intracellular calcium. We demonstrated that the release of ATP was found to be calcium independent because emptying the intracellular calcium stores did not cause ATP release; ATP release was still observed in the absence of external calcium and it persisted on chelating cytosolic calcium. On the other hand, the released ATP activated purinergic receptors and mobilized intracellular calcium stores. The resulting depletion of stored calcium led to the activation of capacitative calcium entry. Increase in cytosolic calcium concentration was blocked by the purinergic receptor blocker suramin, phospholipase C inhibitor and apyrase, which hydrolyses ATP. Collectively, our data demonstrate that human keratinocytes are mechanically activated by hypo-osmotic shock, leading first to the release of ATP, which in turn stimulates purinergic receptors, resulting in the mobilization of intracellular calcium and capacitative calcium entry. These results emphasize the crucial role of ATP signalling in the transduction of mechanical stimuli in human keratinocytes.
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http://dx.doi.org/10.1111/j.1600-0625.2010.01219.xDOI Listing
May 2011

Molecular mechanisms of mechanotransduction in mammalian sensory neurons.

Nat Rev Neurosci 2011 Mar 9;12(3):139-53. Epub 2011 Feb 9.

Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, UMR 6231, Centre National de la Recherche Scientifique, Université de la Méditerranée, CS80011, Boulevard Pierre Dramard, 13344 Marseille Cedex 15, France.

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.
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http://dx.doi.org/10.1038/nrn2993DOI Listing
March 2011

Hepatocyte growth factor-Met signaling is required for Runx1 extinction and peptidergic differentiation in primary nociceptive neurons.

J Neurosci 2010 Sep;30(37):12414-23

Institut de Biologie du Développement de Marseille Luminy, Unite Mixte de Recherche 6216, Centre National de la Recherche Scientifique-Université de la Méditerranée, 13288 Marseille, France.

Nociceptors in peripheral ganglia display a remarkable functional heterogeneity. They can be divided into the following two major classes: peptidergic and nonpeptidergic neurons. Although RUNX1 has been shown to play a pivotal role in the specification of nonpeptidergic neurons, the mechanisms driving peptidergic differentiation remain elusive. Here, we show that hepatocyte growth factor (HGF)-Met signaling acts synergistically with nerve growth factor-tyrosine kinase receptor A to promote peptidergic identity in a subset of prospective nociceptors. We provide in vivo evidence that a population of peptidergic neurons, derived from the RUNX1 lineage, require Met activity for the proper extinction of Runx1 and optimal activation of CGRP (calcitonin gene-related peptide). Moreover, we show that RUNX1 in turn represses Met expression in nonpeptidergic neurons, revealing a bidirectional cross talk between Met and RUNX1. Together, our novel findings support a model in which peptidergic versus nonpeptidergic specification depends on a balance between HGF-Met signaling and Runx1 extinction/maintenance.
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http://dx.doi.org/10.1523/JNEUROSCI.3135-10.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633456PMC
September 2010

A polycystin-2 (TRPP2) dimerization domain essential for the function of heteromeric polycystin complexes.

EMBO J 2010 Apr 18;29(7):1176-91. Epub 2010 Feb 18.

Centre de Recherche en Neurophysiologie et Neurobiologie de Marseille, UMR 6231, CNRS, Université de la Méditerranée, Bd Pierre Dramard, Marseille Cedex 15, France.

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+)-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.
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http://dx.doi.org/10.1038/emboj.2010.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857461PMC
April 2010

Ciliar functions in the nephron.

Pflugers Arch 2009 May 20;458(1):179-87. Epub 2009 Jan 20.

Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, CNRS, UMR, Université de la Méditerranée, France.

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.
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http://dx.doi.org/10.1007/s00424-008-0632-0DOI Listing
May 2009

NGF inhibits M/KCNQ currents and selectively alters neuronal excitability in subsets of sympathetic neurons depending on their M/KCNQ current background.

J Gen Physiol 2008 Jun 12;131(6):575-87. Epub 2008 May 12.

Department of Pharmacology, Hebei Medical University, Shijiazhuang, China 050017.

M/KCNQ currents play a critical role in the determination of neuronal excitability. Many neurotransmitters and peptides modulate M/KCNQ current and neuronal excitability through their G protein-coupled receptors. Nerve growth factor (NGF) activates its receptor, a member of receptor tyrosine kinase (RTK) superfamily, and crucially modulates neuronal cell survival, proliferation, and differentiation. In this study, we studied the effect of NGF on the neuronal (rat superior cervical ganglion, SCG) M/KCNQ currents and excitability. As reported before, subpopulation SCG neurons with distinct firing properties could be classified into tonic, phasic-1, and phasic-2 neurons. NGF inhibited M/KCNQ currents by similar proportion in all three classes of SCG neurons but increased the excitability only significantly in tonic SCG neurons. The effect of NGF on excitability correlated with a smaller M-current density in tonic neurons. The present study indicates that NGF is an M/KCNQ channel modulator and the characteristic modulation of the neuronal excitability by NGF may have important physiological implications.
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http://dx.doi.org/10.1085/jgp.200709924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2391251PMC
June 2008

Formation of a new receptor-operated channel by heteromeric assembly of TRPP2 and TRPC1 subunits.

EMBO Rep 2008 May 7;9(5):472-9. Epub 2008 Mar 7.

University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, Oklahoma 73104, USA.

Although several protein-protein interactions have been reported between transient receptor potential (TRP) channels, they are all known to occur exclusively between members of the same group. The only intergroup interaction described so far is that of TRPP2 and TRPC1; however, the significance of this interaction is unknown. Here, we show that TRPP2 and TRPC1 assemble to form a channel with a unique constellation of new and TRPP2/TRPC1-specific properties. TRPP2/TRPC1 is activated in response to G-protein-coupled receptor activation and shows a pattern of single-channel conductance, amiloride sensitivity and ion permeability distinct from that of TRPP2 or TRPC1 alone. Native TRPP2/TRPC1 activity is shown in kidney cells by complementary gain-of-function and loss-of-function experiments, and its existence under physiological conditions is supported by colocalization at the primary cilium and by co-immunoprecipitation from kidney membranes. Identification of the heteromultimeric TRPP2/TRPC1 channel has implications in mechanosensation and cilium-based Ca(2+) signalling.
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http://dx.doi.org/10.1038/embor.2008.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373364PMC
May 2008

Mechanosensor Channels in Mammalian Somatosensory Neurons.

Sensors (Basel) 2007 Sep 3;7(9):1667-1682. Epub 2007 Sep 3.

Laboratoire de Neurophysiologie Cellulaire, Centre National de la Recherche Scientifique UMR 6150, Université de la Méditerranée, Marseille, France.

Mechanoreceptive sensory neurons innervating the skin, skeletal muscles andviscera signal both innocuous and noxious information necessary for proprioception, touchand pain. These neurons are responsible for the transduction of mechanical stimuli intoaction potentials that propagate to the central nervous system. The ability of these cells todetect mechanical stimuli impinging on them relies on the presence of mechanosensitivechannels that transduce the external mechanical forces into electrical and chemical signals.Although a great deal of information regarding the molecular and biophysical properties ofmechanosensitive channels in prokaryotes has been accumulated over the past two decades,less is known about the mechanosensitive channels necessary for proprioception and thesenses of touch and pain. This review summarizes the most pertinent data onmechanosensitive channels of mammalian somatosensory neurons, focusing on theirproperties, pharmacology and putative identity.
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http://dx.doi.org/10.3390/s7091667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841838PMC
September 2007