TRPM3 channel activation inhibits contraction of the isolated human ureter via CGRP released from sensory nerves

  • Life Sci. 2021 Mar 1;268:118967. doi: 10.1016/j.lfs.2020.118967.
Jiaxin Liu  1 ,  Mengmeng Zhao  2 ,  Zhenghao Chen  2 ,  Yang Xu  2 ,  Liqiang Guo  2 ,  Shaoyong Wang  2 ,  Yan Li  3 ,  Benkang Shi  3 ,  Xiulin Zhang  4 ,  Xiao-Dong Jin  5
Affiliations
  • 1. The First Affiliated Hospital, College of Medicine, Zhejiang University, China.
  • 2. Department of Urology, The Second Hospital, Cheeloo College of Medicine, Shandong University, China.
  • 3. Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, China.
  • 4. Department of Urology, The Second Hospital, Cheeloo College of Medicine, Shandong University, China. Electronic address: [email protected].
  • 5. The First Affiliated Hospital, College of Medicine, Zhejiang University, China. Electronic address: [email protected].
PMID: 33417951 DOI: 10.1016/j.lfs.2020.118967
Abstract

Aims: Sensory nerve activation modulates ureteral contractility by releasing neuropeptides including CGRP and neurokinin A (NKA). TRPM3 is a recently discovered thermosensitive channel expressed in nociceptive sensory neurons, and plays a key role in heat nociception and chronic pain. The aim of this study is to examine the role of TRPM3 activation in human ureter motility.

Main method: Human proximal ureters were obtained from fourteen patients undergoing nephrectomy. Spontaneous or NKA-evoked contractions of longitudinal ureter strips were recorded in an organ bath. Ureteral TRPM3 expression was examined by immunofluorescence.

Key findings: Spontaneous contractions were observed in 60% of examined strips. TRPM3 activation using pregnenolone sulphate (PS) or CIM0216 (specific TRPM3 agonists) dose-dependently reduced the frequency of spontaneous and NKA-evoked contractions, with IC50s of 241.7 μM and 4.4 μM, respectively. The inhibitory actions of TRPM3 agonists were mimicked by CGRP (10 to 100 nM) or a cAMP analogue (8-Br-cAMP; 1 mM). The inhibitory actions of TRPM3 agonists (300 μM PS or 30 μM CIM0216) were blocked by pretreatment with primidone (TRPM3 antagonist; 30 μM), tetrodotoxin (Sodium Channel blocker; 1 μM), olcegepant (CGRP Receptor antagonist; 10 μM), or H89 (non-specific PKA inhibitor; 30 μM). TRPM3 was co-expressed with CGRP in nerves in the sub-urothelial and intermuscular regions of the ureter.

Significance: TRPM3 channels expressed on sensory terminals of the human ureter involve in inhibitory sensory neurotransmission and modulate ureter motility via the CGRP-cAMP-PKA signal pathway. Targeting TRPM3 may be a pharmacological strategy for promoting the ureter stone passage.

Keywords
CGRP; Pregnenolone sulphate; Sensory afferents; TRPM3 channel; Ureteral motility.
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