G protein-coupled receptor 55 activated by palmitoylethanolamide is associated with the development of nocturia associated with circadian rhythm disorders

Tatsuya Ihara; Youichi Shinozaki; Eiji Shigetomi; Yosuke Danjo; Sachiko Tsuchiya; Mie Kanda; Manabu Kamiyama; Masayuki Takeda; Schuichi Koizumi; Takahiko Mitsui

doi:10.1016/j.lfs.2023.122072

G protein-coupled receptor 55 activated by palmitoylethanolamide is associated with the development of nocturia associated with circadian rhythm disorders

Life Sci. 2023 Nov 1:332:122072. doi: 10.1016/j.lfs.2023.122072. Epub 2023 Sep 11.

Authors

Affiliations

¹ Department of Urology, Toranomon Hospital Kajigaya, Kawasaki, Kanagawa 213-8587, Japan. Electronic address: tihara@toranomon.gr.jp.
² Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
³ Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
⁴ Department of Urology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
⁵ Department of Urology, Toranomon Hospital Kajigaya, Kawasaki, Kanagawa 213-8587, Japan.

PMID: 37704067
DOI: 10.1016/j.lfs.2023.122072

Abstract

Aims: Bladder function is regulated by clock genes and dysregulation of circadian bladder function can cause nocturia. The blood concentration of palmitoylethanolamide (PEA), a fatty acid metabolite, changes with circadian rhythm. Clock gene abnormalities demonstrate the highest PEA levels during the sleep phase. PEA is a GPR55 agonist that influences urination; therefore, increased PEA during the sleep phase may cause nocturia. Herein, we investigated the function of GPR55 to evaluate the relationship between GPR55 and nocturia that evoked higher PEA during the sleep phase in patients with circadian rhythm disorders.

Main methods: Male C57BL/6 mice were used. GPR55 localization was evaluated by immunofluorescence staining, qRT-PCR, and western blotting. Variations in PEA-induced intracellular Ca²⁺ concentrations were measured in primary cultured mouse urothelial cells (UCs) using Ca²⁺ imaging. PEA-induced NGF and PGI₂ release in UCs was measured by ELISA. The micturition reflex pathway after PEA administration was evaluated using immunofluorescence staining.

Key findings: GPR55 was predominant in the UC layer. PEA induced release of Ca²⁺ from the endoplasmic reticulum into the UC cytoplasm. ELISA and immunofluorescence staining revealed that NGF and PGI₂ were released from bladder UCs, stimulated the pontine micturition center in mice, and induced nocturia.

Significance: The loss of regular circadian metabolizing rhythm in fatty acids causes higher blood PEA levels during the sleep phase. Binding of PEA to GPR55 in UC may activate the downstream processes of the micturition reflex, leading to nocturia. These findings suggest a new mechanism for nocturia and its potential as a therapeutic target.

Keywords: Circadian rhythm; Fatty acid metabolite; GPR55; Nocturia; Palmitoylethanolamide.