1. Academic Validation
  2. TRPM3 channel activation inhibits contraction of the isolated human ureter via CGRP released from sensory nerves

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

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: zhangxiulin1965@163.com.
  • 5 The First Affiliated Hospital, College of Medicine, Zhejiang University, China. Electronic address: xiaodong-jin@zju.edu.cn.
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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