title: Response of the human detrusor to stretch is regulated by TREK-1, a two-pore-domain (K2P) mechano-gated potassium channel.
abstract: The mechanisms of mechanosensitivity underlying the response of the human bladder to stretch are poorly understood. Animal data suggest that stretch-activated two-pore-domain (K2P) K(+) channels play a critical role in bladder relaxation during the filling phase. The objective of this study was to characterize the expression and function of stretch-activated K2P channels in the human bladder and to clarify their physiological role in bladder mechanosensitivity. Gene and protein analysis of the K2P channels TREK-1, TREK-2 and TRAAK in the human bladder revealed that TREK-1 is the predominantly expressed member of the mechano-gated subfamily of K2P channels. Immunohistochemical labelling of bladder wall identified higher levels of expression of TREK-1 in detrusor smooth muscle cells in comparison to bladder mucosa. Functional characterization and biophysical properties of the predominantly expressed member of the K2P family, the TREK-1 channel, were evaluated by in vitro organ bath studies and the patch-clamp technique. Electrophysiological recordings from single smooth muscle cells confirmed direct activation of TREK-1 channels by mechanical stretch and negative pressure applied to the cell membrane. Inhibition of TREK-1 channels in the human detrusor significantly delayed relaxation of the stretched bladder smooth muscle strips and triggered small-amplitude spontaneous contractions. Application of negative pressure to cell-attached patches (-20 mmHg) caused a 19-fold increase in the open probability (NPo) of human TREK-1 channels. l-Methionine (1 mm), a specific TREK-1 inhibitor, dramatically decreased the NPo of TREK-1 channels from 0.045 ± 0.003 to 0.008 ± 0.001 (n = 8, P ≤ 0.01). Subsequent addition of arachidonic acid (10 μm), a channel opener, increased the open probability of methionine-inhibited unitary currents up to 0.43 ± 0.05 at 0 mV (n = 9, P ≤ 0.05). The results of our study provide direct evidence that the response of the human detrusor to mechanical stretch is regulated by activation of mechano-gated TREK-1 channels. Impaired mechanosensation and mechanotransduction associated with the changes in stretch-activated K2P channels may underlie myogenic bladder dysfunction in humans.
authors.affiliation: Division of Urology, Department of Surgery, University of Pennsylvania, PA, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Lei
authors.affiliation: Division of Urology, Department of Surgery, University of Pennsylvania, PA, USA.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Pan
authors.affiliation: Department of Surgery, Cooper University, NJ, USA.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Chang
authors.affiliation: Division of Urology, Department of Surgery, University of Pennsylvania, PA, USA.
authors.forename: S Bruce
authors.initials: SB
authors.lastname: Malkowicz
authors.affiliation: Division of Urology, Department of Surgery, University of Pennsylvania, PA, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Guzzo
authors.affiliation: Division of Urology, Department of Surgery, University of Pennsylvania, PA, USA anna.malykhina@uphs.upenn.edu.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Malykhina
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000378:metabolism / Q000502:physiology*; D015221:Potassium Channels / Q000502:physiology; D024683:Potassium Channels, Tandem Pore Domain / Q000502:physiology*; D001743:Urinary Bladder / Q000378:metabolism / Q000502:physiology*
chemical_list: C503438:KCNK10 protein, human; C503432:KCNK4 protein, human; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1