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Sandoz G.,University of Nice Sophia Antipolis | Sandoz G.,Laboratories of Excellence | Levitz J.,University of California at Berkeley
Frontiers in Molecular Neuroscience | Year: 2013

Optogenetic tools were originally designed to target specific neurons for remote control of their activity by light and have largely been built around opsin-based channels and pumps. These naturally photosensitive opsins are microbial in origin and are unable to mimic the properties of native neuronal receptors and channels. Over the last 8 years, photoswitchabletethered ligands (PTLs) have enabled fast and reversible control of mammalian ion channels, allowing optical control of neuronal activity. One such PTL, MAQ, contains a maleimide (M) to tether the molecule to a genetically engineered cysteine, a photoisomerizable azobenzene (A) linker and a pore-blocking quaternary ammonium group (Q). MAQ was originally used to photo-control SPARK, an engineered light-gated potassium channel derived from Shaker. Potassium channel photo-block by MAQ has recently been extended to a diverse set of mammalian potassium channels including channels in the voltage-gated and K2P families. Photoswitchable potassium channels, which maintain native properties, pave the way for the optical control of specific aspects of neuronal function and for high precision probing of a specific channel's physiological functions. To extend optical control to natively expressed channels, without overexpression, one possibility is to develop a knock-in mouse in which the wild type channel gene is replaced by its light-gated version. Alternatively, the recently developed photoswitchable-conditional-subunit technique (PCS) provides photocontrol of the channel of interest by molecular replacement of wild type complexes. Finally, photochromic ligands (PCLs) also allow photocontrol of potassium channels without genetic manipulation using soluble compounds. In this review we discuss different techniques for optical control of native potassium channels and their associated advantages and disadvantages. © 2013 Sandoz and Levitz. Source


Lalli E.,French National Center for Scientific Research | Lalli E.,University of Nice Sophia Antipolis | Barhanin J.,French National Center for Scientific Research | Barhanin J.,Laboratories of Excellence | And 3 more authors.
Trends in Endocrinology and Metabolism | Year: 2016

Primary aldosteronism (PA) is caused by excessive production of aldosterone by the adrenal cortex and is determined by a benign aldosterone-producing adenoma (APA) in a significant proportion of cases. Local mechanisms, as opposed to circulatory ones, that control aldosterone production in the adrenal cortex are particularly relevant in the physiopathological setting and in the pathogenesis of PA. A breakthrough in our understanding of the pathogenetic mechanisms in APA has been the identification of somatic mutations in genes controlling membrane potential and intracellular calcium concentrations. However, recent data show that the processes of nodule formation and aldosterone hypersecretion can be dissociated in pathological adrenals and suggest a model envisaging different molecular events for the pathogenesis of APA. © 2016 Elsevier Ltd. Source


Bandulik S.,University of Regensburg | Tauber P.,University of Regensburg | Lalli E.,University of Nice Sophia Antipolis | Barhanin J.,University of Nice Sophia Antipolis | And 2 more authors.
Pflugers Archiv European Journal of Physiology | Year: 2015

The physiological control of steroid hormone secretion from the adrenal cortex depends on the function of potassium channels. The “two-pore domain K+ channels” (K2P) TWIK-related acid sensitive K+ channel 1 (TASK1), TASK3, and TWIK-related K+ channel 1 (TREK1) are strongly expressed in adrenocortical cells. They confer a background K+ conductance to these cells which is important for the K+ sensitivity as well as for angiotensin II and adrenocorticotropic hormone-dependent stimulation of aldosterone and cortisol synthesis. Mice with single deletions of the Task1 or Task3 gene as well as Task1/Task3 double knockout mice display partially autonomous aldosterone synthesis. It appears that TASK1 and TASK3 serve different functions: TASK1 affects cell differentiation and prevents expression of aldosterone synthase in the zona fasciculata, while TASK3 controls aldosterone secretion in glomerulosa cells. TREK1 is involved in the regulation of cortisol secretion in fasciculata cells. These data suggest that a disturbed function of K2P channels could contribute to adrenocortical pathologies in humans. © 2014, The Author(s). Source


Cazals Y.,Aix - Marseille University | Bevengut M.,Aix - Marseille University | Zanella S.,Aix - Marseille University | Brocard F.,Aix - Marseille University | And 3 more authors.
Nature Communications | Year: 2015

In the cochlea, Kt is essential for mechano-electrical transduction. Here, we explore cochlear structure and function in mice lacking Kt channels of the two-pore domain family. A profound deafness associated with a decrease in endocochlear potential is found in adult Kcnk5-/- mice. Hearing occurs around postnatal day 19 (P19), and completely disappears 2 days later. At P19, Kcnk5-/- mice have a normal endolymphatic [Kt] but a partly lowered endocochlear potential. Using Lac-Z as a gene reporter, KCNK5 is mainly found in outer sulcus Claudius̈, Boettcheŕs and root cells. Low levels of expression are also seen in the spiral ganglion, Reissneŕs membrane and stria vascularis. Essential channels (KCNJ10 and KCNQ1) contributing to Kt secretion in stria vascularis have normal expression in Kcnk5-/- mice. thus, KCNK5 channels are indispensable for the maintenance of hearing. Among several plausible mechanisms, we emphasize their role in Kt recycling along the outer sulcus lateral route. © 2015 Macmillan Publishers Limited. All rights reserved. Source


Bayliss D.A.,University of Virginia | Barhanin J.,University of Nice Sophia Antipolis | Barhanin J.,Laboratories of Excellence | Gestreau C.,Aix - Marseille University | Guyenet P.G.,University of Virginia
Pflugers Archiv European Journal of Physiology | Year: 2015

A number of the subunits within the family of K2P background K+ channels are sensitive to changes in extracellular pH in the physiological range, making them likely candidates to mediate various pH-dependent processes. Based on expression patterns within several brainstem neuronal cell groups that are believed to function in CO2/H+ regulation of breathing, three TASK subunits—TASK-1, TASK-2, and TASK-3—were specifically hypothesized to contribute to this central respiratory chemoreflex. For the acid-sensitive TASK-1 and TASK-3 channels, despite widespread expression at multiple levels within the brainstem respiratory control system (including presumptive chemoreceptor populations), experiments in knockout mice provided no evidence for their involvement in CO2 regulation of breathing. By contrast, the alkaline-activated TASK-2 channel has a more restricted brainstem distribution and was localized to the Phox2b-expressing chemoreceptor neurons of the retrotrapezoid nucleus (RTN). Remarkably, in a Phox2b27Ala/+ mouse genetic model of congenital central hypoventilation syndrome (CCHS) that is characterized by reduced central respiratory chemosensitivity, selective ablation of Phox2b-expressing RTN neurons was accompanied by a corresponding loss of TASK-2 expression. Furthermore, genetic deletion of TASK-2 blunted RTN neuronal pH sensitivity in vitro, reduced alkaline-induced respiratory network inhibition in situ and diminished the ventilatory response to CO2/H+ in vivo. Notably, a subpopulation of RTN neurons from TASK-2−/− mice retained their pH sensitivity, at least in part due to a residual pH-sensitive background K+ current, suggesting that other mechanisms (and perhaps other K2P channels) for RTN neuronal pH sensitivity are yet to be identified. © 2014, Springer-Verlag Berlin Heidelberg. Source

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