MONNA, a Potent and Selective Blocker for Transmembrane Protein with Unknown Function 16/Anoctamin-1

Oh, Soo Jin; Hwang, Seok Jin; Jung, Jonghoon; Yu, Kuai; Jeongyeon, Kim; Choi, Jung Yoon; Hartzell, H. Criss; Roh, Eun Joo; Lee, C. Justin

doi:10.1124/mol.113.087502

Cited by 111 publications

(94 citation statements)

References 22 publications

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“…6B). Similarly, intraprostatic injections (days 1, 5, and 9) of ANO1 inhibitors with some nonspecific activity as well, T16Ainh-A01, CaCCinh-A01, and MONNA (300 μM in 50 μL per rat) (28)(29)(30), significantly reduced the prostate weights of BPH model rats (Fig. 6C).…”

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Anoctamin 1 (TMEM16A) is essential for testosterone-induced prostate hyperplasia

Young

Wee

Jung

et al. 2015

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

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Benign prostatic hyperplasia (BPH) is characterized by an enlargement of the prostate, causing lower urinary tract symptoms in elderly men worldwide. However, the molecular mechanism underlying the pathogenesis of BPH is unclear. Anoctamin1 (ANO1) encodes a Ca 2+ -activated chloride channel (CaCC) that mediates various physiological functions. Here, we demonstrate that it is essential for testosterone-induced BPH. ANO1 was highly amplified in dihydrotestosterone (DHT)-treated prostate epithelial cells, whereas the selective knockdown of ANO1 inhibited DHT-induced cell proliferation. Three androgen-response elements were found in the ANO1 promoter region, which is relevant for the DHTdependent induction of ANO1. Administration of the ANO1 blocker or Ano1 small interfering RNA, inhibited prostate enlargement and reduced histological abnormalities in vivo. We therefore concluded that ANO1 is essential for the development of prostate hyperplasia and is a potential target for the treatment of BPH.enign prostatic hyperplasia (BPH) is characterized by the anatomical enlargement of the prostate gland and is one of the most common diseases among elderly men (1). More than 50% of men aged more than 60 suffer from lower urinary tract symptoms, including urinary hesitancy, weak stream, and nocturia, which are commonly caused by bladder obstruction (2). The availability of testosterone or dihydrotestosterone (DHT) is known to cause the development of histologically characterized BPH (3). Clinical reports on BPH have suggested a positive association between BPH and prostate cancer, with increased risk of and mortality from prostate cancer among BPH patients (4). However, some epidemiologic studies have reported that BPH is not a cause of prostate cancer (5). Despite the controversy on the association between prostate cancer and BPH, common risk factors for the two diseases include chronic inflammation, metabolic disturbance, and genetic variation (6, 7). Regardless of its association with prostate cancer, BPH is still a social issue for the elderly, but the etiologic mechanisms of its pathology remain unknown. Anoctamin1 (ANO1, also known as TMEM16A) encodes a Ca 2+ -activated chloride channel (CaCC) (8-10), and is widely expressed in secretory epithelia, including the salivary gland, trachea (11), and intestine, smooth muscle (12), and sensory neurons (13). ANO1 is known to mediate various physiological functions, such as fluid and electrolyte secretion, gut motility, vascular smooth muscle contraction, and thermal nociception (14).ANO1 has been suggested to be a regulator of cell proliferation and tumorigenesis, even before it was discovered as a CaCC, and is highly expressed in several carcinomas, including gastrointestinal stromal tumors (15), esophageal squamous cell carcinoma (16), head and neck squamous cell carcinoma (17), oral cancer (18), breast cancer (19), and prostate cancer (20). The disruption of Ano1 or the administration of a pharmacological ANO1 inhibitor impairs the proliferation of interstitial cells of Ca...

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Section: Significancementioning

confidence: 99%

“…3 B, C, E, and F). Similarly, ANO1 blockers, such as tannic acid, T16inh-A01, CaCCinh-A01, and MONNA (28)(29)(30), also effectively inhibited the DHTinduced proliferation of LnCap cells (Fig. 3G).…”

Section: Significancementioning

confidence: 99%

Anoctamin 1 (TMEM16A) is essential for testosterone-induced prostate hyperplasia

Young

Wee

Jung

et al. 2015

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

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“…Unfortunately, these compounds lack specificity and high affinity. Other blockers, such as eugenol [38], digallic and tannic acids [39], benzbromarone [40], CaCC inh -A01 [41] and the novel T16A inh -A01 [42] and MONNA [43], have been identified recently. The investigation of their specificity and blocking mode is still in progress.…”

Section: Introductionmentioning

confidence: 98%

Multiple effects of anthracene-9-carboxylic acid on the TMEM16B/anoctamin2 calcium-activated chloride channel

Cherian

Menini

Boccaccio

2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Ca(2+)-activated Cl(-) currents (CaCCs) play important roles in many physiological processes. Recent studies have shown that TMEM16A/anoctamin1 and TMEM16B/anoctamin2 constitute CaCCs in several cell types. Here we have investigated for the first time the extracellular effects of the Cl(-) channel blocker anthracene-9-carboxylic acid (A9C) and of its non-charged analogue anthracene-9-methanol (A9M) on TMEM16B expressed in HEK 293T cells, using the whole-cell patch-clamp technique. A9C caused a voltage-dependent block of outward currents and inhibited a larger fraction of the current as depolarization increased, whereas the non-charged A9M produced a small, not voltage dependent block of outward currents. A similar voltage-dependent block by A9C was measured both when TMEM16B was activated by 1.5 and 13μM Ca(2+). However, in the presence of 1.5μM Ca(2+) (but not in 13μM Ca(2+)), A9C also induced a strong potentiation of tail currents measured at -100mV after depolarizing voltages, as well as a prolongation of the deactivation kinetics. On the contrary, A9M did not produce potentiation of tail currents, showing that the negative charge is required for potentiation. Our results provide the first evidence that A9C has multiple effects on TMEM16B and that the negative charge of A9C is necessary both for voltage-dependent block and for potentiation. Future studies are required to identify the molecular mechanisms underlying these complex effects of A9C on TMEM16B. Understanding these mechanisms will contribute to the elucidation of the structure and functional properties of TMEM16B channels.

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“…Using high throughput screening methods, four different groups have identified TMEM16A antagonists: benzbromarone, 14 T16Ainh-A01, 15 MONNA 16 and B25. 17 These groups investigated antagonist activity at TMEM16A with IC 50 ’s of less than 10 μM.…”

Section: Introductionmentioning

confidence: 99%

Antagonists of the TMEM16A Calcium-activated Chloride Channel Modulate Airway Smooth Muscle Tone and Intracellular Calcium

et al. 2015

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Background Perioperative bronchospasm refractory to β-agonists continues to challenge anesthesiologists and intensivists. The TMEM16A calcium-activated chloride channel modulates airway smooth muscle (ASM) contraction. We hypothesized that TMEM16A antagonists would relax ASM contraction by modulating membrane potential and calcium flux. Methods Human ASM, guinea pig tracheal rings or mouse peripheral airways were contracted with acetylcholine (Ach) or leukotriene D4 (LTD4) and then treated with the TMEM16A antagonists: benzbromarone, T16Ainh-A01, MONNA or B25. In separate studies, guinea pig tracheal rings were contracted with Ach and then exposed to increasing concentrations of isoproterenol (0.01nM-10μM) ± benzbromarone. Plasma membrane potential and intracellular calcium concentrations were measured in human ASM cells. Results Benzbromarone was the most potent TMEM16A antagonist tested for relaxing an Ach-induced contraction in guinea pig tracheal rings (n=6). Further studies were done to investigate benzbromarone’s clinical utility. In human ASM, benzbromarone relaxed either an acetylcholine- or LTD4-induced contraction (n=8). Benzbromarone was also effective in relaxing peripheral airways (n=9) and potentiating relaxation by β-agonists (n=5–10). In cellular mechanistic studies, benzbromarone hyperpolarized human ASM cells (n=9–12) and attenuated intracellular calcium flux from both the plasma membrane and sarcoplasmic reticulum (n=6–12). Conclusions TMEM16A antagonists work synergistically with β-agonists and through a novel pathway of interrupting ion flux both at the plasma membrane and sarcoplasmic reticulum to acutely relax human airway smooth muscle.

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MONNA, a Potent and Selective Blocker for Transmembrane Protein with Unknown Function 16/Anoctamin-1

Cited by 111 publications

References 22 publications

Anoctamin 1 (TMEM16A) is essential for testosterone-induced prostate hyperplasia

Anoctamin 1 (TMEM16A) is essential for testosterone-induced prostate hyperplasia

Multiple effects of anthracene-9-carboxylic acid on the TMEM16B/anoctamin2 calcium-activated chloride channel

Antagonists of the TMEM16A Calcium-activated Chloride Channel Modulate Airway Smooth Muscle Tone and Intracellular Calcium

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