Activation of TRPM8 channel inhibits contraction of the isolated human ureter

Abstract

Aims:The transient receptor potential melastin-8 (TRPM8) channel is a "cooling" receptor expressed in primary sensory neurons and can be activated by compounds like menthol or icilin. TRPM8 is involved in the regulation of urinary bladder sensory function and contraction, but the role of TRPM8 in the ureter, particularly in the human ureter, is poorly understood. The aim of this study is to examine the effects of TRPM8 activation on human ureter contraction. Methods: Human ureters were acquired from 20 patients undergoing radical nephrectomy. Contractions of ureter strips were recorded by an isometric transducer in the organ bath. Ureteral TRPM8 expression in the human ureter was examined by immunofluorescence and western blot. Results:The two TRPM8 agonists menthol and icilin both reduced the frequency of spontaneous, electrical field stimulation, or neurokinin A-evoked ureteral contractions in a dose-dependent manner. The inhibitory effects were decreased by 10-fold in mucosa-denuded strips. The inhibitory effects of TRPM8 agonists were mimicked by calcitonin gene-related peptide (CGRP), and were blocked by KRP2579 (a TRPM8 antagonist), tetrodotoxin (a sodium channel blocker), olcegepant (BIBN, a CGRP receptor antagonist), SQ22536 (an adenylate cyclase antagonist), or H89 (a nonspecific cAMP-dependent protein kinase A inhibitor). TRPM8 was coexpressed with CGRP on the nerves located in the suburothelial and intermuscular regions and was not expressed in the urothelium. Conclusions: The TRPM8 channel expressed on sensory nerve terminals of the human ureter is involved in the inhibitory sensory neurotransmission and modulate ureter contraction via the CGRP-adenylyl cyclase-protein kinase A pathway. TRPM8 may be involved in stone-induced changes in ureter contraction or pain.

Functional roles for PIEZO1 and PIEZO2 in urothelial mechanotransduction and lower urinary tract interoception

“…These analyses were performed as described previously ( 76 ), using the modifications described in the Supplemental Methods.…”

The adaptive evolution of cold‐activated TRPM8 in wildlife vertebrates

“…One explanation is that conserving TRPM8 cold activation is harmless for marine mammals. Accordingly, TRPM8 participate in acute cold‐induced urinary urgency, cold‐induced mucus hypersecretion in lung, ureter contraction, innate immunity, and acrosome reaction (Gibbs et al, 2011; de Jong et al, 2015; Khalil et al, 2016; Li et al, 2011; Liu et al, 2021; Martínez‐López et al, 2011; Nocchi et al, 2014; Uvin et al, 2015). Therefore, the conserved thermal sensitivity of TRPM8s is reserved in marine mammals partially due to some indispensable physiological processes mediated by TRPM8.…”

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

“…In fact, some TRPM8 antagonists have been studied on this pain condition, as commented in the corresponding section. TRPM8 channels were also found in the ureter sensory nerve terminals, where they modulate ureter contraction and play an inhibitory role in sensory neurotransmission, through the CGRP-adenyl cyclase-PKA pathway [104]. Mechanical sciatic nerve (MSN) injury in mice produces increased apoptosis, Ca 2+ entry, and mitochondrial reactive oxygen species (ROS) generation by the nerve lesion.…”