Presynaptic Localization and Possible Function of Calcium-Activated Chloride Channel Anoctamin 1 in the Mammalian Retina

Jeon, Ji Hyun; Paik, Sang Hyun; Chun, Myung-Hoon; Oh, Uhtaek; Kim, In‐Beom

doi:10.1371/journal.pone.0067989

Cited by 29 publications

(33 citation statements)

References 57 publications

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“…Thus, TMEM16A appears essential for exocytosis. A role of different TMEM16 paralogues for synaptic transmission has been proposed recently (33)(34)(35). We examined TMEM16A-expressing HEK293 cells and noticed this enhanced membrane capacitance.…”

Section: Tmem16a Controls Intracellular Ca 2+ Signals and Membrane Exmentioning

confidence: 78%

TMEM16A is indispensable for basal mucus secretion in airways and intestine

et al. 2018

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Transmembrane member 16A (TMEM16A) is the Ca2+‐activated chloride channel in airways and intestine. It has been associated with goblet cell metaplasia, as expression of TMEM16A is strongly up‐regulated in cystic fibrosis and asthma during mucus hypersecretion. However, the possible role of TMEM16A for mucus production or mucus secretion remains obscure, and whether TMEM16A controls the function of intestinal goblet cells is entirely unknown. Basal mucus secretion in lungs occurs through low levels of ATP in the airway surface liquid. Here, we report for the first time that TMEM16A is essential for basal secretion of mucus in airways and intestine. Airway‐ciliated and intestinal epithelial‐specific knockout of TMEM16A (TMEM16Aflox/floxFoxJ1, TMEM16Aflox/floxVil1) leads to accumulation of mucus in airway club (Clara) cells and intestinal goblet cells, respectively. Acute ATP‐induced mucus secretion by airway club cells is inhibited when TMEM16A is knocked out in ciliated cells, possibly as a result of compromised release of prosecretory cytokines. Knockdown or inhibition of TMEM16A in human Calu3 airway epithelial cells indicates compromised IL‐8 release. In intestinal goblet cells lacking expression of TMEM16A, mucus accumulates as a result of compromised ATP‐induced secretion. In contrast, cholinergic mucus secretion by compound exocytosis is independent of TMEM16A. The data demonstrate a previously unrecognized role of TMEM16A for membrane exocytosis and describe a novel, ATP‐driven pathway for intestinal mucus secretion. We conclude that ATP‐dependent mucus secretion in both airways and intestine requires TMEM16A. The present results may form the basis for a novel, therapeutic approach for the treatment of mucus hypersecretion in inflammatory airway and intestinal disease.—Benedetto, R., Cabrita, I., Schreiber, R., Kunzelmann, K. TMEM16A is indispensable for basal mucus secretion in airways and intestine. FASEB J. 33, 4502–4512 (2019). http://www.fasebj.org

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Section: Tmem16a Controls Intracellular Ca 2+ Signals and Membrane Exmentioning

confidence: 78%

TMEM16A is indispensable for basal mucus secretion in airways and intestine

et al. 2018

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“…The channels do not show pronounced inactivation and are thought to serve as a link in a feedback regulatory chain that limits transmitter release (Thoreson et al, 2000, 2002, 2003; Mercer et al, 2011). ANO 1 channels have been reported to be expressed in rod and cone terminals (Mercer et al, 2011; Jeon et al, 2013). We have recently found that ANO 2 is specifically expressed in rod terminals and absent from cone photoreceptors, which suggests a distinct role in the regulation of transmitter release under scotopic conditions (Dauner et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Calmodulin-dependent activation and inactivation of anoctamin calcium-gated chloride channels

Vocke

Dauner

Hahn

et al. 2013

Journal of General Physiology

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Calcium-dependent chloride channels serve critical functions in diverse biological systems. Driven by cellular calcium signals, the channels codetermine excitatory processes and promote solute transport. The anoctamin (ANO) family of membrane proteins encodes three calcium-activated chloride channels, named ANO 1 (also TMEM16A), ANO 2 (also TMEM16B), and ANO 6 (also TMEM16F). Here we examined how ANO 1 and ANO 2 interact with Ca2+/calmodulin using nonstationary current analysis during channel activation. We identified a putative calmodulin-binding domain in the N-terminal region of the channel proteins that is involved in channel activation. Binding studies with peptides indicated that this domain, a regulatory calmodulin-binding motif (RCBM), provides two distinct modes of interaction with Ca2+/calmodulin, one at submicromolar Ca2+ concentrations and one in the micromolar Ca2+ range. Functional, structural, and pharmacological data support the concept that calmodulin serves as a calcium sensor that is stably associated with the RCBM domain and regulates the activation of ANO 1 and ANO 2 channels. Moreover, the predominant splice variant of ANO 2 in the brain exhibits Ca2+/calmodulin-dependent inactivation, a loss of channel activity within 30 s. This property may curtail ANO 2 activity during persistent Ca2+ signals in neurons. Mutagenesis data indicated that the RCBM domain is also involved in ANO 2 inactivation, and that inactivation is suppressed in the retinal ANO 2 splice variant. These results advance the understanding of Ca2+ regulation in anoctamin Cl− channels and its significance for the physiological function that anoctamin channels subserve in neurons and other cell types.

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“…The tail current of the hERG was not significantly changed after 5 min of 0.1% DMSO (95.170.7% of the control, n ¼12). Western blot analyses were performed with minor modifications, as described previously (Jeon et al, 2013). Briefly, cells were homogenized in ice-cold RIPA buffer (50 mM Tris buffer, pH 8.0; 150 mM NaCl; 1% NP-40; 0.5% deoxycholate; and 0.1% SDS).…”

Section: Methodsmentioning

confidence: 99%