Altered expression and modulation of the two-pore-domain (K2P) mechanogated potassium channel TREK-1 in overactive human detrusor
| Autor: | Ricardo H. Pineda, Shandra Wilson, Balachandar Nedumaran, Randall B. Meacham, Anna P. Malykhina, Xiao-Qing Pan, Joseph A. Hypolite |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty endocrine system Physiology media_common.quotation_subject Myocytes Smooth Muscle Down-Regulation Biology Urination Caveolins 03 medical and health sciences Potassium Channels Tandem Pore Domain Smooth muscle Internal medicine medicine Humans RNA Small Interfering Cytoskeleton media_common Urinary bladder Mechanosensation Urinary Bladder Overactive medicine.disease Potassium channel 030104 developmental biology medicine.anatomical_structure Endocrinology Overactive bladder human activities Research Article |
| Popis: | Detrusor overactivity (DO) is the abnormal response of the urinary bladder to physiological stretch during the filling phase of the micturition cycle. The mechanisms of bladder smooth muscle compliance upon the wall stretch are poorly understood. We previously reported that the function of normal detrusor is regulated by TREK-1, a member of the mechanogated subfamily of two-pore-domain potassium (K2P) channels. In the present study, we aimed to identify the changes in expression and function of TREK-1 channels under pathological conditions associated with DO, evaluate the potential relationship between TREK-1 channels and cytoskeletal proteins in the human bladder, and test the possibility of modulation of TREK-1 channel expression by small RNAs. Expression of TREK-1 channels in DO specimens was 2.7-fold decreased compared with control bladders and was associated with a significant reduction of the recorded TREK-1 currents. Isolated DO muscle strips failed to relax when exposed to a TREK-1 channel opener. Immunocytochemical labeling revealed close association of TREK-1 channels with cell cytoskeletal proteins and caveolins, with caveolae microdomains being severely disrupted in DO specimens. Small activating RNA (saRNA) tested in vitro provided evidence that expression of TREK-1 protein could be partially upregulated. Our data confirmed a significant downregulation of TREK-1 expression in human DO specimens and provided evidence of close association between the channel, cell cytoskeleton, and caveolins. Upregulation of TREK-1 expression by saRNA could be a future step for the development of in vivo pharmacological and genetic approaches to treat DO in humans. |
| Databáze: | OpenAIRE |
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