Novel regulatory mechanism in human urinary bladder

Central role of transient receptor potential melastatin 4 channels in detrusor smooth muscle function

Kiril L. Hristov, Amy C. Smith, Shankar P. Parajuli, John Malysz, Eric S. Rovner, Georgi Petkov

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Transient receptor potential melastatin 4 (TRPM4) channels are Ca2+-activated nonselective cation channels that have been recently identified as regulators of detrusor smooth muscle (DSM) function in rodents. However, their expression and function in human DSM remain unexplored. We provide insights into the functional role of TRPM4 channels in human DSM under physiological conditions. We used a multidisciplinary experimental approach, including RT-PCR, Western blotting, immunohistochemistry and immunocytochemistry, patch-clamp electrophysiology, and functional studies of DSM contractility. DSM samples were obtained from patients without preoperative overactive bladder symptoms. RT-PCR detected mRNA transcripts for TRPM4 channels in human DSM whole tissue and freshly isolated single cells. Western blotting and immunohistochemistry with confocal microscopy revealed TRPM4 protein expression in human DSM. Immunocytochemistry further detected TRPM4 protein expression in DSM single cells. Patch-clamp experiments showed that 9-phenanthrol, a selective TRPM4 channel inhibitor, significantly decreased the transient inward cation currents and voltage step-induced whole cell currents in freshly isolated human DSM cells. In current-clamp mode, 9-phenanthrol hyperpolarized the human DSM cell membrane potential. Furthermore, 9-phenanthrol attenuated the spontaneous phasic, carbachol-induced and nerve-evoked contractions in human DSM isolated strips. Significant species-related differences in TRPM4 channel activity between human, rat, and guinea pig DSM were revealed, suggesting a more prominent physiological role for the TRPM4 channel in the regulation of DSM function in humans than in rodents. In conclusion, TRPM4 channels regulate human DSM excitability and contractility and are critical determinants of human urinary bladder function. Thus, TRPM4 channels could represent promising novel targets for the pharmacological or genetic control of overactive bladder.

Original languageEnglish (US)
Pages (from-to)C600-C611
JournalAmerican Journal of Physiology - Cell Physiology
Volume310
Issue number7
DOIs
StatePublished - Apr 1 2016

Fingerprint

Smooth Muscle
Urinary Bladder
Immunohistochemistry
Smooth Muscle Myocytes
Overactive Urinary Bladder
Cations
Rodentia
Western Blotting
Polymerase Chain Reaction
Electrophysiology
Carbachol
Human Activities
Confocal Microscopy
Membrane Potentials
Guinea Pigs
Proteins
Cell Membrane
Pharmacology
Muscles
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology

Cite this

Novel regulatory mechanism in human urinary bladder : Central role of transient receptor potential melastatin 4 channels in detrusor smooth muscle function. / Hristov, Kiril L.; Smith, Amy C.; Parajuli, Shankar P.; Malysz, John; Rovner, Eric S.; Petkov, Georgi.

In: American Journal of Physiology - Cell Physiology, Vol. 310, No. 7, 01.04.2016, p. C600-C611.

Research output: Contribution to journalArticle

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