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

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 mu M and 4.4 mu M, 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 mu M PS or 30 mu M CIM0216) were blocked by pretreatment with primidone (TRPM3 antagonist; 30 mu M), tetrodotoxin (sodium channel blocker; 1 mu M), olcegepant (CGRP receptor antagonist; 10 mu M), or H89 (non-specific PKA inhibitor; 30 mu M). 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.