Pd03-03 Both Activator and Inhibitor of Transient Receptor Potential Mucolipin 1 (Trpml1) Inhibit Contractions Induced by Various Stimuli in Human Prostate Smooth Muscle

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology (PD03)1 May 2024PD03-03 BOTH ACTIVATOR AND INHIBITOR OF TRANSIENT RECEPTOR POTENTIAL MUCOLIPIN 1 (TRPML1) INHIBIT CONTRACTIONS INDUCED BY VARIOUS STIMULI IN HUMAN PROSTATE SMOOTH MUSCLE Sheng Hu, Nikolaus Eitelberger, Ayhanim Elif Müderrisoglu, Christian G. Stief, Martin Hennenberg, and Alexander J. Tamalunas Sheng HuSheng Hu , Nikolaus EitelbergerNikolaus Eitelberger , Ayhanim Elif MüderrisogluAyhanim Elif Müderrisoglu , Christian G. StiefChristian G. Stief , Martin HennenbergMartin Hennenberg , and Alexander J. TamalunasAlexander J. Tamalunas View All Author Informationhttps://doi.org/10.1097/01.JU.0001009388.01015.e5.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: TRPML1 is a Ca2+ channel localized on late endosomes and lysosomes. Recent research has uncovered a novel role for TRPML1 in contraction of mouse bladder and urethral smooth muscles, which involves Ca2+ spark-activated large-conductance K+ channels. An analog role of TRPML1 in smooth muscle contraction of the prostate has not yet been considered. Here, we investigated effects of a TRPML1 inhibitor and of an activator on contractions of human prostate tissues. METHODS: Prostate tissues were obtained from patients undergoing radical prostatectomy. Contractions were induced by electric field stimulation (EFS), α1-adrenergic agonists (phenylephrine, methoxamine, noradrenaline), endothelin-1 or the thromboxane A2 analog U46619, or by cumulative concentrations of calcium chloride in calcium-free Krebs-Henseleit solution in an organ bath. RESULTS: The TRPML1 synthetic activator 1 (MLSA1) inhibited contractions induced by EFS, phenylephrine, noradrenaline and U46619 by approximately 20% (Figure 1A-D). Interestingly, the TRPML1 synthetic inhibitor 3 (MLSI3) showed inhibitory effects on contractions induced by EFS, phenylephrine, methoxamine and endothelin-1 as well. Inhibitions seen with MLSI3 were partly substantial, exceeding 70% inhibition for several concentrations of methoxamine and phenylephrine (Figure 1E-H). Using a calcium-free Krebs-Henseleit solution and following depletion of intracellular calcium stores, neither MLSA1 nor MLSI3 inhibited contractions induced by calcium chloride (Figure 1I and J). CONCLUSIONS: Interestingly, inhibitors and activators of TRPML1 inhibit neurogenic and agonist-induced contractions, suggesting an essential role of TRPML1 in prostate smooth muscle contraction. Lacking effects on calcium-induced contractions in Ca2+-free solution demonstrate central functions in calcium handling. Inhibition by the activator may be explained by depletion of calcium after TRPML1 activation, preventing calcium-dependent contractions by agonists. Inhibitions of the inhibitor may be explained by inhibition of cytosolic calcium elevations, again preventing calcium-dependent contractions by agonists. Download PPT Source of Funding: None © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e77 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Sheng Hu More articles by this author Nikolaus Eitelberger More articles by this author Ayhanim Elif Müderrisoglu More articles by this author Christian G. Stief More articles by this author Martin Hennenberg More articles by this author Alexander J. Tamalunas More articles by this author Expand All Advertisement PDF downloadLoading ...