Involvement of TRPM4 in detrusor overactivity following spinal cord transection in mice

Kullmann, F. Aura; Jm, Beckel; McDonnell, Bronagh; Gauthier, C; Am, Lynn; Zabbarova,; Ikeda, Youko; Wc, de Groat; La, Birder

doi:10.1007/s00210-018-1542-0

Cited by 21 publications

(25 citation statements)

References 77 publications

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“…These studies have suggested that TRPM4 could be a potential therapeutic target for detrusor overactivity. In line with this, Kullmann et al [83] investigating the potential role of TRPM4 in detrusor overactivity following spinal cord transection (SCT) in mice, found that TRPM4 was upregulated in the urothelium and detrusor smooth muscle after the lesion. The spontaneous contractile activity of detrusor muscle strips in both spinally intact and STC mice was significantly reduced.…”

Section: Trpm4 and Bladder Functionmentioning

confidence: 81%

TRP Channels as Lower Urinary Tract Sensory Targets

Andersson

2019

Medical Sciences

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Several members of the transient receptor potential (TRP) superfamily, including TRPV1, TRPV2, TRPV4, TRM4, TRPM8 and TRPA1, are expressed in the lower urinary tract (LUT), not only in neuronal fibers innervating the bladder and urethra, but also in the urothelial and muscular layers of the bladder and urethral walls. In the LUT, TRP channels are mainly involved in nociception and mechanosensory transduction. Animal studies have suggested the therapeutic potential of several TRP channels for the treatment of both bladder over- and underactivity and bladder pain disorders,; however translation of this finding to clinical application has been slow and the involvement of these channels in normal human bladder function, and in various pathologic states have not been established. The development of selective TRP channel agonists and antagonists is ongoing and the use of such agents can be expected to offer new and important information concerning both normal physiological functions and possible therapeutic applications.

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Section: Trpm4 and Bladder Functionmentioning

confidence: 81%

TRP Channels as Lower Urinary Tract Sensory Targets

Andersson

2019

Medical Sciences

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“…Although TRPM4 channels have recently been detected in mouse urinary bladder whole tissue and isolated single DSM cells [28], the involvement of these channels in cholinergic responses has not been reported. Furthermore, the information about the functional role of TRPM4 channels in the gastrointestinal system is limited.…”

Section: Discussionmentioning

confidence: 99%

Involvement of transient receptor potential melastatin 4 channels in the resting membrane potential setting and cholinergic contractile responses in mouse detrusor and ileal smooth muscles

Alom

Matsuyama

Nagano

et al. 2019

The Journal of Veterinary Medical Science

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Here, we investigated the effects of 9-hydroxyphenanthrene (9-phenanthrol), a potent and selective transient receptor potential melastatin 4 (TRPM4) channel blocker, on the resting membrane potential and cholinergic contractile responses to elucidate the functional role of TRPM4 channels in the contractile activities of mouse detrusor and ileal longitudinal smooth muscles. We observed that, 9-phenanthrol (3–30 µ M) did not significantly inhibit high K + -induced contractions in both preparations; however, 9-phenanthrol (10 µ M) strongly inhibited cholinergic contractions evoked by electrical field stimulation in detrusor preparations compared to inhibitions in ileal preparations. 9-Phenanthrol (10 µ M) significantly inhibited the muscarinic agonist, carbachol-induced contractile responses and slowed the maximum upstroke velocities of the contraction in detrusor preparations. However, the agent (10 µ M) did not inhibit the contractions due to intracellular Ca 2+ release evoked by carbachol, suggesting that the inhibitory effect of 9-phenanthrol may primarily be due to the inhibition of the membrane depolarization process incurred by TRPM4 channels. On the other hand, 9-phenanthrol (10 µ M) did not affect carbachol-induced contractile responses in ileal preparations. Further, 9-phenanthrol (10 µ M) significantly hyperpolarized the resting membrane potential and decreased the basal tone in both detrusor and ileal muscle preparations. Taken together, our results suggest that TRPM4 channels are constitutively active and are involved in setting of the resting membrane potential, thereby regulating the basal tone in detrusor and ileal smooth muscles. Thus, TRPM4 channels play a significant role in cholinergic signaling in detrusor, but not ileal, smooth muscles.

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“…Urinary mucosa, defined as urothelium and lamina propria, was surgically separated from the smooth muscle, homogenized using Lysing Matrix D in a FastPrep 24 instrument (MP Biomedicals, Solon, OH) following previously established protocols . Equal amounts of proteins were separated on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS‐PAGE) gels and transferred to polyvinylidene fluoride membranes, which were then incubated overnight at 4°C with primary antibodies (Table ) followed by secondary antibodies (donkey anti‐rabbit horseradish peroxidase [1:5000] or sheep anti‐mouse horseradish peroxidase [1:5000]; GE Amersham, Pittsburgh, PA) for 1 hour in 5% (w/v) milk TBS‐T, incubated in WesternBright Quantum (Advansta, Menlo Park, CA) and then imaged on a ChemiDoc MP (Bio‐Rad).…”

Section: Methodsmentioning

confidence: 99%

Acute spinal cord injury is associated with mitochondrial dysfunction in mouse urothelium

Kullmann

Truschel

McDonnell

et al. 2019

Neurourology and Urodynamics

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Aim To characterize the effects of acute spinal cord injury (SCI) on mitochondrial morphology and function in bladder urothelium and to test the therapeutic efficacy of early treatment with the mitochondrially targeted antioxidant, MitoTempo. Methods We used a mouse model of acute SCI by spinal cord transection between the T8‐T9 vertebrae with or without MitoTempo delivery at the time of injury followed by tissue processing at 3 days after SCI. Control, SCI, and SCI‐MitoTempo‐treated mice were compared in all experimental conditions. Assessments included analysis of markers of mitochondrial health including accumulation of reactive oxygen species (ROS), morphological changes in the ultrastructure of mitochondria by transmission electron microscopy, and Western blot analysis to quantify protein levels of markers for autophagy and altered mitochondrial dynamics. Results SCI resulted in an increase in oxidative stress markers and ROS production, confirming mitochondrial dysfunction. Mitochondria from SCI mice developed large electron‐dense inclusions and these aberrant mitochondria accumulated throughout the cytoplasm suggesting an inability to clear dysfunctional mitochondria by mitophagy. SCI mice also exhibited elevated levels of dynamin‐related protein 1 (DRP1), consistent with a disruption of mitochondrial dynamics. Remarkably, treatment with MitoTempo reversed many of the SCI‐induced abnormalities that we observed. Conclusions Acute SCI negatively and severely affects mitochondrial health of bladder urothelium. Early treatment of SCI with MitoTempo may be a viable therapeutic agent to mitigate these deleterious effects.

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Involvement of TRPM4 in detrusor overactivity following spinal cord transection in mice

Cited by 21 publications

References 77 publications

TRP Channels as Lower Urinary Tract Sensory Targets

TRP Channels as Lower Urinary Tract Sensory Targets

Involvement of transient receptor potential melastatin 4 channels in the resting membrane potential setting and cholinergic contractile responses in mouse detrusor and ileal smooth muscles

Acute spinal cord injury is associated with mitochondrial dysfunction in mouse urothelium

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