No abstract

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...

Touch sensation or proprioception requires the transduction of mechanical stimuli into electrical signals by mechanoreceptors in the periphery. These mechanoreceptors are equipped with various transducer channels. Although Piezo1 and 2 are mechanically activated (MA) channels with rapid inactivation, MA molecules with other inactivation kinetics have not been identified. Here we report that heterologously expressed Tentonin3 (TTN3)/TMEM150C is activated by mechanical stimuli with distinctly slow inactivation kinetics. Genetic ablation of Ttn3/Tmem150c markedly reduced slowly adapting neurons in dorsal-root ganglion neurons. The MA TTN3 currents were inhibited by known blockers of mechanosensitive ion channels. Moreover, TTN3 was localized in muscle spindle afferents. Ttn3-deficient mice exhibited the loss of coordinated movements and abnormal gait. Thus, TTN3 appears to be a component of a mechanosensitive channel with a slow inactivation rate and contributes to motor coordination. Identification of this gene advances our understanding of the various types of mechanosensations, including proprioception.

Highlights d Tentonin 3/TMEM150C (TTN3) is expressed specifically in murine pancreatic b-cells d TTN3 mediates b-cell swelling upon glucose stimulation and hypotonicity d TTN3 mediates cation current influx upon glucose stimulation and hypotonicity d Genetic ablation of TTN3 in b-cells impairs insulin secretion by glucose