Franck C. Chatelain
University of Nice Sophia Antipolis
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Featured researches published by Franck C. Chatelain.
Nature | 2004
Filip Van Petegem; Kimberly A. Clark; Franck C. Chatelain; Daniel L. Minor
Voltage-gated calcium channels (CaVs) govern muscle contraction, hormone and neurotransmitter release, neuronal migration, activation of calcium-dependent signalling cascades, and synaptic input integration. An essential CaV intracellular protein, the β-subunit (CaVβ), binds a conserved domain (the α-interaction domain, AID) between transmembrane domains I and II of the pore-forming α1 subunit and profoundly affects multiple channel properties such as voltage-dependent activation, inactivation rates, G-protein modulation, drug sensitivity and cell surface expression. Here, we report the high-resolution crystal structures of the CaVβ2a conserved core, alone and in complex with the AID. Previous work suggested that a conserved region, the β-interaction domain (BID), formed the AID-binding site; however, this region is largely buried in the CaVβ core and is unavailable for protein–protein interactions. The structure of the AID–CaVβ2a complex shows instead that CaVβ2a engages the AID through an extensive, conserved hydrophobic cleft (named the α-binding pocket, ABP). The ABP–AID interaction positions one end of the CaVβ near the intracellular end of a pore-lining segment, called IS6, that has a critical role in CaV inactivation. Together, these data suggest that CaVβs influence CaV gating by direct modulation of IS6 movement within the channel pore.
Cell | 2009
Reza Sharif-Naeini; Joost H.A. Folgering; Delphine Bichet; Fabrice Duprat; Inger Lauritzen; Malika Arhatte; Martine Jodar; Alexandra Dedman; Franck C. Chatelain; Uwe Schulte; Kevin Retailleau; Laurent Loufrani; Amanda Patel; Frederick Sachs; Patrick Delmas; Dorien J.M. Peters; Eric Honoré
Autosomal-dominant polycystic kidney disease, the most frequent monogenic cause of kidney failure, is induced by mutations in the PKD1 or PKD2 genes, encoding polycystins TRPP1 and TRPP2, respectively. Polycystins are proposed to form a flow-sensitive ion channel complex in the primary cilium of both epithelial and endothelial cells. However, how polycystins contribute to cellular mechanosensitivity remains obscure. Here, we show that TRPP2 inhibits stretch-activated ion channels (SACs). This specific effect is reversed by coexpression with TRPP1, indicating that the TRPP1/TRPP2 ratio regulates pressure sensing. Moreover, deletion of TRPP1 in smooth muscle cells reduces SAC activity and the arterial myogenic tone. Inversely, depletion of TRPP2 in TRPP1-deficient arteries rescues both SAC opening and the myogenic response. Finally, we show that TRPP2 interacts with filamin A and demonstrate that this actin crosslinking protein is critical for SAC regulation. This work uncovers a role for polycystins in regulating pressure sensing.
Proceedings of the National Academy of Sciences of the United States of America | 2009
Guillaume Sandoz; Dominique Douguet; Franck C. Chatelain; Michel Lazdunski; Florian Lesage
Mechanosensitive K+ channels TREK1 and TREK2 form a subclass of two P-domain K+ channels. They are potently activated by polyunsaturated fatty acids and are involved in neuroprotection, anesthesia, and pain perception. Here, we show that acidification of the extracellular medium strongly inhibits TREK1 with an apparent pK near to 7.4 corresponding to the physiological pH. The all-or-none effect of pH variation is steep and is observed within one pH unit. TREK2 is not inhibited but activated by acidification within the same range of pH, despite its close homology with TREK1. A single conserved residue, H126 in TREK1 and H151 in TREK2, is involved in proton sensing. This histidine is located in the M1P1 extracellular loop preceding the first P domain. The differential effect of acidification, that is, activation for TREK2 and inhibition for TREK1, involves other residues located in the P2M4 loop, linking the second P domain and the fourth membrane-spanning segment. Structural modeling of TREK1 and TREK2 and site-directed mutagenesis strongly suggest that attraction or repulsion between the protonated side chain of histidine and closely located negatively or positively charged residues in P2M4 control outer gating of these channels. The differential sensitivity of TREK1 and TREK2 to external pH variations discriminates between these two K+ channels that otherwise share the same regulations by physical and chemical stimuli, and by hormones and neurotransmitters.
Journal of Biological Chemistry | 2010
Sylvain Feliciangeli; Magalie P. Tardy; Guillaume Sandoz; Franck C. Chatelain; Richard Warth; Saïd Bendahhou; Florian Lesage
Tandem of P domains in a weak inwardly rectifying K+ channel 1 (TWIK1) is a K+ channel that produces unusually low levels of current. Replacement of lysine 274 by a glutamic acid (K274E) is associated with stronger currents. This mutation would prevent conjugation of a small ubiquitin modifier peptide to Lys-274, a mechanism proposed to be responsible for channel silencing. However, we found no biochemical evidence of TWIK1 sumoylation, and we showed that the conservative change K274R did not increase current, suggesting that K274E modifies TWIK1 gating through a charge effect. Now we rule out an eventual effect of K274E on TWIK1 trafficking, and we provide convincing evidence that TWIK1 silencing results from its rapid retrieval from the cell surface. TWIK1 is internalized via a dynamin-dependent mechanism and addressed to the recycling endosomal compartment. Mutation of a diisoleucine repeat located in its cytoplasmic C terminus (I293A,I294A) stabilizes TWIK1 at the plasma membrane, resulting in robust currents. The effects of I293A,I294A on channel trafficking and of K274E on channel activity are cumulative, promoting even more currents. Activation of serotoninergic receptor 5-HT1R or adrenoreceptor α2A-AR stimulates TWIK1 but has no effect on TWIK1I293A,I294A, suggesting that Gi protein activation is a physiological signal for increasing the number of active channels at the plasma membrane.
Proceedings of the National Academy of Sciences of the United States of America | 2012
Franck C. Chatelain; Delphine Bichet; Dominique Douguet; Sylvain Feliciangeli; Saïd Bendahhou; Markus Reichold; Richard Warth; Florian Lesage
TWIK1 belongs to the family of background K+ channels with two pore domains. In native and transfected cells, TWIK1 is detected mainly in recycling endosomes. In principal cells in the kidney, TWIK1 gene inactivation leads to the loss of a nonselective cationic conductance, an unexpected effect that was attributed to adaptive regulation of other channels. Here, we show that TWIK1 ion selectivity is modulated by extracellular pH. Although TWIK1 is K+ selective at neutral pH, it becomes permeable to Na+ at the acidic pH found in endosomes. Selectivity recovery is slow after restoration of a neutral pH. Such hysteresis makes plausible a role of TWIK1 as a background channel in which selectivity and resulting inhibitory or excitatory influences on cell excitability rely on its recycling rate between internal acidic stores and the plasma membrane. TWIK1−/− pancreatic β cells are more polarized than control cells, confirming a depolarizing role of TWIK1 in kidney and pancreatic cells.
Neuron | 2005
Franck C. Chatelain; Noga Alagem; Qiang Xu; Raika Pancaroglu; Eitan Reuveny; Daniel L. Minor
Ion channels lower the energetic barrier for ion passage across cell membranes and enable the generation of bioelectricity. Electrostatic interactions between permeant ions and channel pore helix dipoles have been proposed as a general mechanism for facilitating ion passage. Here, using genetic selections to probe interactions of an exemplar potassium channel blocker, barium, with the inward rectifier Kir2.1, we identify mutants bearing positively charged residues in the potassium channel signature sequence at the pore helix C terminus. We show that these channels are functional, selective, resistant to barium block, and have minimally altered conductance properties. Both the experimental data and model calculations indicate that barium resistance originates from electrostatics. We demonstrate that potassium channel function is remarkably unperturbed when positive charges occur near the permeant ions at a location that should counteract pore helix electrostatic effects. Thus, contrary to accepted models, the pore helix dipole seems to be a minor factor in potassium channel permeation.
Proceedings of the National Academy of Sciences of the United States of America | 2008
Jörg Balss; Panagiotis Papatheodorou; Mario Mehmel; Dirk Baumeister; Brigitte Hertel; Nicolas Delaroque; Franck C. Chatelain; Daniel L. Minor; James L. Van Etten; Joachim Rassow; Anna Moroni; Gerhard Thiel
K+ channels operate in the plasma membrane and in membranes of organelles including mitochondria. The mechanisms and topogenic information for their differential synthesis and targeting is unknown. This article describes 2 similar viral K+ channels that are differentially sorted; one protein (Kesv) is imported by the Tom complex into the mitochondria, the other (Kcv) to the plasma membrane. By creating chimeras we discovered that mitochondrial sorting of Kesv depends on a hierarchical combination of N- and C-terminal signals. Crucial is the length of the second transmembrane domain; extending its C terminus by ≥2 hydrophobic amino acids redirects Kesv from the mitochondrial to the plasma membrane. Activity of Kesv in the plasma membrane is detected electrically or by yeast rescue assays only after this shift in sorting. Hence only minor structural alterations in a transmembrane domain are sufficient to switch sorting of a K+ channel between the plasma membrane and mitochondria.
PLOS ONE | 2009
Franck C. Chatelain; Sabrina Gazzarrini; Yuichiro Fujiwara; Cristina Arrigoni; Courtney K. Domigan; Giuseppina Ferrara; Carlos Pantoja; Gerhard Thiel; Anna Moroni; Daniel L. Minor
Background Understanding the interactions between ion channels and blockers remains an important goal that has implications for delineating the basic mechanisms of ion channel function and for the discovery and development of ion channel directed drugs. Methodology/Principal Findings We used genetic selection methods to probe the interaction of two ion channel blockers, barium and amantadine, with the miniature viral potassium channel Kcv. Selection for Kcv mutants that were resistant to either blocker identified a mutant bearing multiple changes that was resistant to both. Implementation of a PCR shuffling and backcrossing procedure uncovered that the blocker resistance could be attributed to a single change, T63S, at a position that is likely to form the binding site for the inner ion in the selectivity filter (site 4). A combination of electrophysiological and biochemical assays revealed a distinct difference in the ability of the mutant channel to interact with the blockers. Studies of the analogous mutation in the mammalian inward rectifier Kir2.1 show that the T→S mutation affects barium block as well as the stability of the conductive state. Comparison of the effects of similar barium resistant mutations in Kcv and Kir2.1 shows that neighboring amino acids in the Kcv selectivity filter affect blocker binding. Conclusions/Significance The data support the idea that permeant ions have an integral role in stabilizing potassium channel structure, suggest that both barium and amantadine act at a similar site, and demonstrate how genetic selections can be used to map blocker binding sites and reveal mechanistic features.
European Journal of Medicinal Chemistry | 2014
Nuno Rodrigues; Khalil Bennis; Delphine Vivier; Vanessa Pereira; Franck C. Chatelain; Eric Chapuy; Hemantkumar Deokar; Jérôme Busserolles; Florian Lesage; Alain Eschalier; Sylvie Ducki
The TWIK-related K(+) channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs. It has been reported that TREK-1 -/- mice were more sensitive than wild-type mice to painful stimuli, suggesting that activation of TREK-1 could result in pain inhibition. Here we report the synthesis of a series of substituted caffeate esters (12a-u) based on the hit compound CDC 2 (cinnamyl 3,4-dihydroxyl-α-cyanocinnamate). These analogs were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid induced-writhing assay) leading to the identification a series of novel molecules able to activate TREK-1 and displaying potent analgesic activity in vivo.
Trends in Pharmacological Sciences | 2014
Haijun Chen; Franck C. Chatelain; Florian Lesage
K(+) channels play a key role in regulating cellular excitability. It was thought that the strong K(+) selectivity of these channels was static, only altered by mutations in their selectivity filter, which can cause severe genetic disorders. Recent studies demonstrate that selectivity of K(+) channels can also exhibit dynamic changes. Under acidic conditions or in low extracellular K(+) concentrations, the two-pore domain K(+) channel (K2P) TWIK1 becomes permeable to Na(+), shifting from an inhibitory role to an excitatory role. This phenomenon is responsible for the paradoxical depolarization of human cardiomyocytes in pathological hypokalemia, and therefore may contribute to cardiac arrhythmias. In other cell types, TWIK1 produces depolarizing leak currents under physiological conditions. Dynamic ion selectivity also occurs in other K2P channels. Here we review evidence that dynamic selectivity of K2P channels constitutes a new regulatory mechanism of cellular excitability, whose significance is only now becoming appreciated.