Available online 11 February 2023, 107525
Author links open overlay panel, , , , , , , , AbstractTMEM16A, a member of the TMEM16 family, is the molecular basis of Ca2+-activated chloride channels (CaCCs) and is involved in a variety of physiological and pathological processes. Previous studies have focused more on respiratory-related diseases and tumors. However, recent studies have identified an important role for TMEM16A in cardiovascular diseases, especially in pulmonary hypertension. TMEM16A is expressed in both pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs) and is involved in the development of pulmonary hypertension. This paper presents the structure and function of TMEM16A, the pathogenesis of pulmonary hypertension, and highlights the role and mechanism of TMEM16A in pulmonary hypertension, summarizing the controversies in this field and taking into account hypertension and portal hypertension, which have similar pathogenesis. It is hoped that the unique role of TMEM16A in pulmonary hypertension will be illustrated and provide ideas for research in this area.
Section snippetsThe TMEM16 family of membrane proteins and TMEM16AThe TMEM16 (Transmembrane protein 16) family of membrane proteins is also known as the Anoctamin (ANO) family. The TMEM16 family contains 10 family members, TMEM16A to TMEM16K (ANO1-ANO10), except TMEM16I. Members of this family are subdivided into three sub-families TMEM16A/TMEM16B, TMEM16C/TMEM16D/TMEM16J, and TMEM16E/TMEM16F based on structural and functional similarities, and a unique branch, TMEM16G [1]. In addition, TMEM16H and TMEM16K in the TMEM16 family appear to have separated early
The definition of Pulmonary HypertensionPulmonary hypertension (PH) is a chronic and progressive disease that, like many other lung diseases, often leads to delays in diagnosis and therefore in optimal treatment [47]. Pulmonary hypertension is a major global health problem and is by no means uncommon. All age groups are affected, but it is more common in women, people aged 75 years or older, and Black individuals [48]. Current estimates suggest that the prevalence of pulmonary hypertension is about 1% of the global population, and in
The Inhibitors of TMEM16ASince TMEM16A was shown to be the molecular basis of calcium-activated chloride channels, researchers have been working to find specific drugs that can modulate TMEM16A to provide help in the treatment of clinically relevant diseases. The current study suggests two different types of inhibitors of TMEM16A (Table 3), the first group is natural products, mainly represented by traditional Chinese medicine compounds, including Gallotannins, Tannic acid [72], Eugenol [73], Matrine [74], Plumbagin
Conclusion and prospectIon channels play essential roles in human physiology and toxicology. Cardiac contraction, neural transmission, temperature sensing, insulin release, regulation of apoptosis, cellular pH, and oxidative stress, as well as detection of active compounds from chili, are some of the processes in which ion channels have an important role. [90] Among ion channels, calcium-activated chloride channels (CaCCs) play a particularly important role in cellular physiology, including epithelial secretion of
Uncited LinksFigure 2, Table 2
Declaration of Competing InterestThe authors have no competing interests to declare that are relevant to the content of this article.
AcknowledgementsThis study was supported by the grants from National Natural Science Foundation of China (No. 81971820).
Reference (92)M. KondoNiflumic acid inhibits goblet cell degranulation in a guinea pig asthma modelAllergol Int
(2012)
A.K. DuttaIdentification and functional characterization of TMEM16A, a Ca2+-activated Cl- channel activated by extracellular nucleotides, in biliary epitheliumJ Biol Chem
(2011)
J. SuzukiCalcium-dependent phospholipid scramblase activity of TMEM16 protein family membersJ Biol Chem
(2013)
Y. Liu et al.The Ca(2+)-activated chloride channel ANO1/TMEM16A: An emerging therapeutic target for epithelium-originated diseases?Acta Pharm Sin B
(2021)
B.C. SchroederExpression cloning of TMEM16A as a calcium-activated chloride channel subunitCell
(2008)
L.C. Schlichter et al.Electrical responses of immature and mature Rana pipiens oocytes to sperm and other activating stimuliDev Biol
(1981)
V. Kalienkova et al.The Groovy TMEM16 Family: Molecular Mechanisms of Lipid Scrambling and Ion ConductionJ Mol Biol
(2021)
M.E. FalzoneKnown structures and unknown mechanisms of TMEM16 scramblases and channelsJ Gen Physiol
(2018)
Y.D. YangTMEM16A confers receptor-activated calcium-dependent chloride conductanceNature
(2008)
A. CaputoTMEM16A, a membrane protein associated with calcium-dependent chloride channel activityScience
(2008)
Y. ZhangInferior Olivary TMEM16B Mediates Cerebellar Motor LearningNeuron
(2017)
S. RascheTmem16b is specifically expressed in the cilia of olfactory sensory neuronsChem Senses
(2010)
H. Kim et al.Investigation of Phosphatidylserine-Transporting Activity of Human TMEM16C IsoformsMembranes (Basel)
(2022)
F. HuangTMEM16C facilitates Na(+)-activated K+ currents in rat sensory neurons and regulates pain processingNat Neurosci
(2013)
T.A. WangTMEM16C is involved in thermoregulation and protects rodent pups from febrile seizuresProc Natl Acad Sci U S A
(2021)
A. BoccaccioLifting the veils on TMEM16E functionChannels (Austin)
(2019)
J. SuzukiCalcium-dependent phospholipid scrambling by TMEM16FNature
(2010)
Z.Q. CuiTMEM16F may be a new therapeutic target for Alzheimer's diseaseNeural Regen Res
(2023)
Y. ZhangTMEM16F phospholipid scramblase mediates trophoblast fusion and placental developmentSci Adv
(2020)
M. Katoh et al.Characterization of human TMEM16G gene in silicoInt J Mol Med
(2004)
R. SchreiberA TMEM16J variant leads to dysregulated cytosolic calcium which may lead to renal diseaseFASEB J
(2023)
I. JunANO9/TMEM16J promotes tumourigenesis via EGFR and is a novel therapeutic target for pancreatic cancerBr J Cancer
(2017)
D.J. HorneCommon polymorphisms in the PKP3-SIGIRR-TMEM16J gene region are associated with susceptibility to tuberculosisJ Infect Dis
(2012)
S.R. BushellThe structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16KNat Commun
(2019)
M. PetkovicTMEM16K is an interorganelle regulator of endosomal sortingNat Commun
(2020)
S. DangCryo-EM structures of the TMEM16A calcium-activated chloride channelNature
(2017)
C. PaulinoActivation mechanism of the calcium-activated chloride channel TMEM16A revealed by cryo-EMNature
(2017)
J.D. BrunnerX-ray structure of a calcium-activated TMEM16 lipid scramblaseNature
(2014)
Q. JiRecent advances in TMEM16A: Structure, function, and diseaseJ Cell Physiol
(2019)
Q. Xiao et al.Acidic amino acids in the first intracellular loop contribute to voltage- and calcium- dependent gating of anoctamin1/TMEM16APLoS One
(2014)
H. ChoThe calcium-activated chloride channel anoctamin 1 acts as a heat sensor in nociceptive neuronsNat Neurosci
(2012)
A. CaputoTMEM16A is associated with voltage-gated calcium channels in mouse retina and its function is disrupted upon mutation of the auxiliary alpha2delta4 subunitFront Cell Neurosci
(2015)
J.H. JeonPresynaptic Localization and Possible Function of Calcium-Activated Chloride Channel Anoctamin 1 in the Mammalian RetinaPLoS One
(2013)
T. HenriquesTMEM16A calcium-activated chloride currents in supporting cells of the mouse olfactory epitheliumJ Gen Physiol
(2019)
J.W. KangSynergistic mucus secretion by histamine and IL-4 through TMEM16A in airway epitheliumAm J Physiol Lung Cell Mol Physiol
(2017)
P. ScudieriAssociation of TMEM16A chloride channel overexpression with airway goblet cell metaplasiaJ Physiol
(2012)
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