Activation of Ca2+‐activated Cl− channel ANO1 by localized Ca2+ signals

Jin, Xin; Shah, Sihab; Du, Xiaona; Zhang, Hailin; Gamper, Nikita

doi:10.1113/jphysiol.2014.275107

Cited by 63 publications

(67 citation statements)

References 106 publications

(279 reference statements)

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“…In the latter model, Ca 2+ release from the ER through IP 3 Rs would provide the Ca 2+ signal required for CaCC activation and Cl − secretion. IP 3 Rs have been shown to colocalize with CaCCs in other cell types such as Xenopus oocytes and nociceptive sensory neurons and may therefore create microdomains with enhanced cytoplasmic [Ca 2+ ] that mediate CaCC activation [77, 79–81]. Such a model is supported by studies in Xenopus oocytes that suggest that Ca 2+ entering the cytosol through CRAC channels is taken up by the ER via SERCA pumps and released by IP 3 Rs at different sites to activate CaCCs [77].…”

Section: Ca2+ Release From Er Stores and Soce In Eccrine Sweat Glamentioning

confidence: 99%

Regulation of epithelial ion transport in exocrine glands by store-operated Ca2+ entry

Concepcion

Feske

2017

Cell Calcium

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Store-operated Ca2+ entry (SOCE) is a conserved mechanism of Ca2+ influx that regulates Ca2+ signaling in many cell types. SOCE is activated by depletion of endoplasmic reticulum (ER) Ca2+ stores in response to physiological agonist stimulation. After it was first postulated by J.W. Putney Jr. in 1986, SOCE has been described in a large number of non-excitable cell types including secretory cells of different exocrine glands. Here we discuss the mechanisms by which SOCE controls salt and fluid secretion in exocrine glands, with a special focus on eccrine sweat glands. In sweat glands, SOCE plays an important, non-redundant role in regulating the function of Ca2+-activated Cl− channels (CaCC), Cl− secretion and sweat production. In the absence of key regulators of SOCE such as the CRAC channel pore subunit ORAI1 and its activator STIM1, the Ca2+-activated chloride channel TMEM16A is inactive and fails to secrete Cl−, resulting in anhidrosis in mice and human patients.

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Section: Ca2+ Release From Er Stores and Soce In Eccrine Sweat Glamentioning

confidence: 99%

Regulation of epithelial ion transport in exocrine glands by store-operated Ca2+ entry

Concepcion

Feske

2017

Cell Calcium

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“…Recent publications, however, raised the possibility that activation of I Cl(Ca) is mediated by a Ca 2+ signal localized at the sarcolemma [20,21]. Moreover, it has turned out that TMEM16A channels are abundantly available in close proximity to IP 3 receptors in nociceptive neurons and to ryanodine receptors (RyRs) in smooth muscle cells [21,22].…”

Section: Introductionmentioning

confidence: 99%

Sarcolemmal Ca 2+ -entry through L-type Ca 2+ channels controls the profile of Ca 2+ -activated Cl − current in canine ventricular myocytes

Horváth

Váczi

Hegyi

et al. 2016

Journal of Molecular and Cellular Cardiology

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Highlights• Ca 2+ -entry via I Ca,L is essential for the activation of I Cl(Ca) • I Cl(Ca) can be activated even in the absence of CICR• TMEM16A and Bestrophin-3 are expressed on human left ventricular muscle• TMEM16A and Bestrophin-3 co-localize with each other and with Ca v 1.2 channels (I Cl(Ca) ) mediated by TMEM16A and/or Bestrophin-3 may contribute to cardiac arrhythmias. The true profile of I Cl(Ca) during an actual ventricular action potential (AP), however, is poorly understood. We aimed to study the profile of I Cl(Ca) systematically under physiological conditions (normal Ca 2+ cycling and AP voltage-clamp) as well as in conditions designed to change [Ca 2+ ] i . The expression of TMEM16A and/or Bestrophin-3 in canine and human left ventricular myocytes was examined. The possible spatial distribution of these proteins and their co-localization with Ca v 1.2 was also studied. The profile of I Cl(Ca), identified as a 9-anthracene carboxylic acid-sensitive current under AP voltageclamp conditions, contained an early fast outward and a late inward component, overlapping early and terminal repolarizations, respectively. Both components were moderately reduced by ryanodine, while fully abolished by BAPTA, but not EGTA. [Ca 2+ ] i was monitored using Fura-2-AM. Setting [Ca 2+ ] i to the systolic level measured in the bulk cytoplasm (1.1 µM) decreased I Cl(Ca), while application of Bay K8644, isoproterenol, and faster stimulation rates increased the amplitude of I Cl(Ca) . Ca 2+ -entry through L-type Ca 2+ channels was essential for activation of I Cl(Ca) . TMEM16A and Bestrophin-3 showed strong co-localization with one another and also with Ca v 1.2 channels, when assessed using immunolabeling and confocal microscopy in both canine myocytes and human ventricular myocardium. Activation of I Cl(Ca) in canine ventricular cells requires Ca 2+ -entry through neighboring L-type Ca 2+ channels and is only augmented by SR Ca 2+ -release. Substantial activation of I Cl(Ca) requires high Ca 2+ in the dyadic clefts which can be effectively buffered by BAPTA, but not EGTA.

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“…Consistent with this, ANO-1 modulation of spiking evoked by current injection is sensitive to intracellular chloride level [51] but demonstration that ANO-1 itself evokes spiking was based on a chloride reversal potential of -18 mV [49]. Given its activation requirements [52], we predicted that ANO-1 channels would not be activated by the GABAergic input underlying PAD; recall that GABA A R activation is necessary for PAD [22]. Nonetheless, to rule out a contribution by ANO-1, we repeated virtual PAD experiments (like in Fig 2) before and after blockade of ANO-1 channels by bath-applied 10 μM T16Ainh-A01 (A01) ( Fig 6 ).…”

Section: Resultsmentioning

confidence: 90%

Combined Changes in Chloride Regulation and Neuronal Excitability Enable Primary Afferent Depolarization to Elicit Spiking without Compromising its Inhibitory Effects

2016

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The central terminals of primary afferent fibers experience depolarization upon activation of GABAA receptors (GABAAR) because their intracellular chloride concentration is maintained above electrochemical equilibrium. Primary afferent depolarization (PAD) normally mediates inhibition via sodium channel inactivation and shunting but can evoke spikes under certain conditions. Antidromic (centrifugal) conduction of these spikes may contribute to neurogenic inflammation while orthodromic (centripetal) conduction could contribute to pain in the case of nociceptive fibers. PAD-induced spiking is assumed to override presynaptic inhibition. Using computer simulations and dynamic clamp experiments, we sought to identify which biophysical changes are required to enable PAD-induced spiking and whether those changes necessarily compromise PAD-mediated inhibition. According to computational modeling, a depolarizing shift in GABA reversal potential (EGABA) and increased intrinsic excitability (manifest as altered spike initiation properties) were necessary for PAD-induced spiking, whereas increased GABAAR conductance density (ḡGABA) had mixed effects. We tested our predictions experimentally by using dynamic clamp to insert virtual GABAAR conductances with different EGABA and kinetics into acutely dissociated dorsal root ganglion (DRG) neuron somata. Comparable experiments in central axon terminals are prohibitively difficult but the biophysical requirements for PAD-induced spiking are arguably similar in soma and axon. Neurons from naïve (i.e. uninjured) rats were compared before and after pharmacological manipulation of intrinsic excitability, and against neurons from nerve-injured rats. Experimental data confirmed that, in most neurons, both predicted changes were necessary to yield PAD-induced spiking. Importantly, such changes did not prevent PAD from inhibiting other spiking or from blocking spike propagation. In fact, since the high value of ḡGABA required for PAD-induced spiking still mediates strong inhibition, we conclude that PAD-induced spiking does not represent failure of presynaptic inhibition. Instead, diminished PAD caused by reduction of ḡGABA poses a greater risk to presynaptic inhibition and the sensory processing that relies upon it.

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Activation of Ca²⁺‐activated Cl⁻ channel ANO1 by localized Ca²⁺ signals

Cited by 63 publications

References 106 publications

Regulation of epithelial ion transport in exocrine glands by store-operated Ca2+ entry

Regulation of epithelial ion transport in exocrine glands by store-operated Ca2+ entry

Sarcolemmal Ca 2+ -entry through L-type Ca 2+ channels controls the profile of Ca 2+ -activated Cl − current in canine ventricular myocytes

Combined Changes in Chloride Regulation and Neuronal Excitability Enable Primary Afferent Depolarization to Elicit Spiking without Compromising its Inhibitory Effects

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