PD03-03: Both Activator and Inhibitor of Transient Receptor Potential Mucolipin 1 (TRPML1) Inhibit Contractions Induced by Various Stimuli in Human Prostate Smooth Muscle.
Friday, May 3, 2024 7:20 AM to 7:30 AM · 10 min. (US/Central)
303A
Abstract
Information
Full Abstract and Figures
Author Block
Sheng Hu, Nikolaus Eitelberger, Ayhanim Elif Müderrisoglu, Christian G. Stief, Martin Hennenberg, Alexander J. Tamalunas*, Munich, Germany
Introduction
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), a1-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% (Fig. 1 A-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 (Fig. 1 E-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 (Fig. 1 I 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.
Source Of Funding
None.
Author Block
Sheng Hu, Nikolaus Eitelberger, Ayhanim Elif Müderrisoglu, Christian G. Stief, Martin Hennenberg, Alexander J. Tamalunas*, Munich, Germany
Introduction
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), a1-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% (Fig. 1 A-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 (Fig. 1 E-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 (Fig. 1 I 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.
Source Of Funding
None.