Muscarinic receptor-induced contractions of the detrusor are impaired in TRPC4 deficient mice

• Published in: Scientific reports Vol. 8; no. 1; pp. 9264 - 11
• Main Authors: Griffin, Caoimhin S., Thornbury, Keith D., Hollywood, Mark A., Sergeant, Gerard P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-06-2018; Nature Publishing Group
• Subjects: 13/51; 14; 38; 38/77; 59; 631/80/86/2372; 64; 64/110; 692/4025/1334; Acetylcholine receptors (muscarinic); Acetylcholinesterase; Calcium channels; Calcium channels (voltage-gated); Calcium influx; Carbachol; Humanities and Social Sciences; Isometric; multidisciplinary; Neostigmine; Potassium chloride; Rodents; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-27617-5

Acetylcholine contracts the bladder by binding to muscarinic M3 receptors on the detrusor, leading to Ca
2+
influx via voltage-gated Ca
2+
channels. The cellular mechanisms linking these events are poorly understood, but studies have suggested that activation of TRPC4 channels could be involved. The purpose of this study was to investigate if spontaneous and cholinergic-mediated contractions of the detrusor were impaired in TRPC4 deficient (TRPC4
−/−
) mice. Isometric tension recordings were made from strips of wild-type (WT) and TRPC4
−/−
detrusor. Spontaneous phasic detrusor contractions were significantly smaller in TRPC4
−/−
mice compared to wild-type, however no difference in response to exogenous application of 60 mM KCl was observed. Cholinergic responses, induced by electric-field stimulation (EFS), bath application of the cholinergic agonist carbachol, or the acetylcholinesterase inhibitor neostigmine were all significantly smaller in TRPC4
−/−
detrusor strips than wild-type. Surprisingly, the TRPC4/5 inhibitor ML204 reduced EFS and CCh-evoked contractions in TRPC4
−/−
detrusor strips. However, TRPC5 expression was up-regulated in these preparations and, in contrast to wild-type, EFS responses were reduced in amplitude by the TRPC5 channel inhibitor clemizole hydrochloride. This study demonstrates that TRPC4 channels are involved in spontaneous and cholinergic-mediated contractions of the murine detrusor. TRPC5 expression is up-regulated in TRPC4
−/−
detrusor strips, and may partially compensate for loss of TRPC4 channels.