TMEM16A channels generate Ca<sup>2+</sup>-activated Cl<sup>−</sup> currents in cerebral artery smooth muscle cells

Thomas-Gatewood, Candice M.; Neeb, Zachary P.; Bulley, Simon; Adebiyi, Adebowale; Bannister, John P.; Leo, M. Dennis; Jaggar, Jonathan H.

doi:10.1152/ajpheart.00404.2011

Cited by 97 publications

(119 citation statements)

References 40 publications

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“…We tested this by determining the effects on insulin secretion of siRNAmediated knockdown of ANO1 gene expression. Treatment with siRNA has been shown to knock down ANO1 RNA and protein expression and to reduce cell membrane chloride currents in various human cell lines (19,31). We treated human islets with ANO1 gene-specific siRNAs for 4.5 d. Incubation of human islets with one of two ANO1-specific siRNAs caused a 50-60% reduction in ANO1 gene expression (Fig.…”

Section: Ins-ano1mentioning

confidence: 98%

Mapping of long-range INS promoter interactions reveals a role for calcium-activated chloride channel ANO1 in insulin secretion

Lefèvre

Гаврилова

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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We used circular chromatin conformation capture (4C) to identify a physical contact in human pancreatic islets between the region near the insulin (INS) promoter and the ANO1 gene, lying 68 Mb away on human chromosome 11, which encodes a Ca 2+ -dependent chloride ion channel. In response to glucose, this contact was strengthened and ANO1 expression increased, whereas inhibition of INS gene transcription by INS promoter targeting siRNA decreased ANO1 expression, revealing a regulatory effect of INS promoter on ANO1 expression. Knockdown of ANO1 expression caused decreased insulin secretion in human islets, establishing a physical proximity-dependent feedback loop involving INS transcription, ANO1 expression, and insulin secretion. To explore a possible role of ANO1 in insulin metabolism, we carried out experiments in Ano1 +/− mice. We observed reduced serum insulin levels and insulin-to-glucose ratios in high-fat diet-fed Ano1 +/− mice relative to Ano1 +/+ mice fed the same diet. Our results show that determination of long-range contacts within the nucleus can be used to detect novel and physiologically relevant mechanisms. They also show that networks of long-range physical contacts are important to the regulation of insulin metabolism.chloride channel | diabetes | insulin secretion

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Section: Ins-ano1mentioning

confidence: 98%

Mapping of long-range INS promoter interactions reveals a role for calcium-activated chloride channel ANO1 in insulin secretion

Lefèvre

Гаврилова

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…2010; Thomas‐Gatewood et al . 2011) and another Ca 2+ ‐dependent Cl − current that requires intracellular cGMP for activation (Matchkov et al . 2004, 2005), which possibly depends on bestrophins (Matchkov et al .…”

Section: Coupling Of Ano1 To Localized Ca2+ Sources In Smooth Musclesmentioning

confidence: 99%

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

Jin

Shah

et al. 2014

The Journal of Physiology

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Ca2+‐activated chloride channels (CaCCs) regulate numerous physiological processes including epithelial transport, smooth muscle contraction and sensory processing. Anoctamin‐1 (ANO1, TMEM16A) is a principal CaCC subunit in many cell types, yet our understanding of the mechanisms of ANO1 activation and regulation are only beginning to emerge. Ca2+ sensitivity of ANO1 is rather low and at negative membrane potentials the channel requires several micromoles of intracellular Ca2+ for activation. However, global Ca2+ levels in cells rarely reach such levels and, therefore, there must be mechanisms that focus intracellular Ca2+ transients towards the ANO1 channels. Recent findings indeed indicate that ANO1 channels often co‐localize with sources of intracellular Ca2+ signals. Interestingly, it appears that in many cell types ANO1 is particularly tightly coupled to the Ca2+ release sites of the intracellular Ca2+ stores. Such preferential coupling may represent a general mechanism of ANO1 activation in native tissues.

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“…Knockdown of TMEM16A in cultured medium-sized cerebral arteries from rat resulted in a reduction of pressure-induced vasoconstriction (19). Moreover whole-cell patch-clamp studies showed that knockdown of TMEM16A attenuated CaCCs in rodent large cerebral artery VSMCs (20,21). However, the role of CaCCs in VSMCs in the regulation of systemic arterial blood pressure could not be addressed so far, as Tmem16a knockout mice have a complex phenotype with early mortality, malformations of the trachea, and intestinal obstruction (22).…”

Section: Introductionmentioning

confidence: 98%

Disruption of vascular Ca2+-activated chloride currents lowers blood pressure

Heinze¹,

Seniuk²,

Sokolov³

et al. 2014

J. Clin. Invest.

134

152

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High blood pressure is the leading risk factor for death worldwide. One of the hallmarks is a rise of peripheral vascular resistance, which largely depends on arteriole tone. Ca 2+ -activated chloride currents (CaCCs) in vascular smooth muscle cells (VSMCs) are candidates for increasing vascular contractility. We analyzed the vascular tree and identified substantial CaCCs in VSMCs of the aorta and carotid arteries. CaCCs were small or absent in VSMCs of medium-sized vessels such as mesenteric arteries and larger retinal arterioles. In small vessels of the retina, brain, and skeletal muscle, where contractile intermediate cells or pericytes gradually replace VSMCs, CaCCs were particularly large. Targeted disruption of the calcium-activated chloride channel TMEM16A, also known as ANO1, in VSMCs, intermediate cells, and pericytes eliminated CaCCs in all vessels studied. Mice lacking vascular TMEM16A had lower systemic blood pressure and a decreased hypertensive response following vasoconstrictor treatment. There was no difference in contractility of medium-sized mesenteric arteries; however, responsiveness of the aorta and small retinal arterioles to the vasoconstrictioninducing drug U46619 was reduced. TMEM16A also was required for peripheral blood vessel contractility, as the response to U46619 was attenuated in isolated perfused hind limbs from mutant mice. Out data suggest that TMEM16A plays a general role in arteriolar and capillary blood flow and is a promising target for the treatment of hypertension.

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TMEM16A channels generate Ca²⁺-activated Cl⁻ currents in cerebral artery smooth muscle cells

Abstract: Thomas-Gatewood C, Neeb ZP, Bulley S, Adebiyi A, Bannister JP, Leo MD, Jaggar JH. TMEM16A channels generate Ca 2ϩ -activated Cl Ϫ currents in cerebral artery smooth muscle cells.

Cited by 97 publications

References 40 publications

Mapping of long-range INS promoter interactions reveals a role for calcium-activated chloride channel ANO1 in insulin secretion

Mapping of long-range INS promoter interactions reveals a role for calcium-activated chloride channel ANO1 in insulin secretion

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

Disruption of vascular Ca2+-activated chloride currents lowers blood pressure

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TMEM16A channels generate Ca2+-activated Cl− currents in cerebral artery smooth muscle cells

Abstract: Thomas-Gatewood C, Neeb ZP, Bulley S, Adebiyi A, Bannister JP, Leo MD, Jaggar JH. TMEM16A channels generate Ca 2ϩ -activated Cl Ϫ currents in cerebral artery smooth muscle cells.

Cited by 97 publications

References 40 publications

Mapping of long-range INS promoter interactions reveals a role for calcium-activated chloride channel ANO1 in insulin secretion

Mapping of long-range INS promoter interactions reveals a role for calcium-activated chloride channel ANO1 in insulin secretion

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

Disruption of vascular Ca2+-activated chloride currents lowers blood pressure

Contact Info

Product

Resources

About

TMEM16A channels generate Ca²⁺-activated Cl⁻ currents in cerebral artery smooth muscle cells

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