MP28-17 SPATIAL AND FUNCTIONAL INTERACTIONS OF THE TRANSIENT RECEPTOR POTENTIAL MELASTATIN-4 CHANNELS AND INOSITOL TRISPHOSPHATE RECEPTORS: NOVEL REGULATORY MECHANISM IN HUMAN DETRUSOR SMOOTH MUSCLE FUNCTION

Abstract

You have accessJournal of UrologyBladder & Urethra: Anatomy, Physiology & Pharmacology I1 Apr 2016MP28-17 SPATIAL AND FUNCTIONAL INTERACTIONS OF THE TRANSIENT RECEPTOR POTENTIAL MELASTATIN-4 CHANNELS AND INOSITOL TRISPHOSPHATE RECEPTORS: NOVEL REGULATORY MECHANISM IN HUMAN DETRUSOR SMOOTH MUSCLE FUNCTION Aaron Provence, Kiril Hristov, Eric Rovner, and Georgi V. Petkov Aaron ProvenceAaron Provence More articles by this author , Kiril HristovKiril Hristov More articles by this author , Eric RovnerEric Rovner More articles by this author , and Georgi V. PetkovGeorgi V. Petkov More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1067AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Transient receptor potential melastatin-4 (TRPM4) channels are emerging as key regulators of human detrusor smooth muscle (DSM) function. However, the cellular mechanisms regulating TRPM4 channel activity in human DSM is virtually unexplored. As a potential cellular mechanism regulating TRPM4 channel activity in human DSM, we have directed our attention to the inositol trisphosphate (IP3) receptors (IP3Rs), which facilitate the release of Ca2+ from the sarcoplasmic reticulum (SR). Since the TRPM4 channels are activated by Ca2+, IP3R-mediated Ca2+ release of the SR represents a potential Ca2+ source for TRPM4 channel activation. Using clinically-characterized human tissues, we investigated the molecular and functional interactions of the TRPM4 channels and IP3Rs in human DSM cells. METHODS In accordance with the approved IRB Pro00045232 of the Medical University of South Carolina, we examined human DSM tissues from 6 donor-patients. Using in situ proximity ligation assay (PLA) and amphotericin-B perforated patch-clamp electrophysiology, we sought to test the hypothesis that TRPM4 channels are tightly associated with the IP3Rs and are activated by IP3R-mediated Ca2+ release of the SR in human DSM. RESULTS As determined by in situ PLA, we demonstrated close co-localization of the TRPM4 channels and IP3Rs in human DSM cells. As the TRPM4 channels and IP3Rs must be located within close apposition to functionally interact, these findings support the concept of a TRPM4-IP3R regulatory mechanism in human DSM function. To investigate IP3R regulation of TRPM4 channel activity, we sought to determine the consequences of IP3R pharmacological inhibition on TRPM4 channel-mediated transient inward cation currents (TICCs). In freshly-isolated human DSM cells, the selective IP3R inhibitor xestospongin C significantly decreased TICCs. These findings suggest that the SR IP3Rs have a key role in mediating the Ca2+-dependent activation of TRPM4 channels in human DSM. CONCLUSIONS In conclusion, this study provides novel insight into the cellular mechanisms regulating TRPM4 channel activity in human DSM function. The study reveals that the TRPM4 channels and IP3Rs are spatially and functionally coupled in human DSM, information that is critical for further evaluating the potential role of the TRPM4 channels as novel therapeutic targets for overactive bladder. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e378 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Aaron Provence More articles by this author Kiril Hristov More articles by this author Eric Rovner More articles by this author Georgi V. Petkov More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...