Integrated signalling networks in the healthy lower urinary tract: A narrative review

Lower urinary tract (LUT) function in health, is summarised in urine storage and voluntary voiding.They are mediated through finely coordinated structural signalling mechanisms.The histological structure of the bladder not only preserves a barrier function but also dynamically senses mechanical and chemical stimuli.Urothelial mechano-transduction comprises stretchactivated channels (ENaC, Piezo1/2, TRPV4) and neurotransmitters such as ATP, nitric oxide and acetylcholine to modulate adjacent afferent nerves.Cholinergic signalling through M3 predominantly muscarinic and nicotinic receptors contributes to sensory and contractile responses.Purinergic P2X and P2Y receptors transduce ATP into sensory firing, whereas nitrergic pathways inhibit C-fibre activation to maintain detrusor quiescence.Additional mediators-including transient receptor potential (TRP) vanilloids; neuropetides; endocannabinoids; endothelins; sex hormones and bradykinin -regulate further the excitability and inflammation of the LUT.Urethra, through multi-layered smooth and striated musculature, supported by the pelvic floor, detects flow and pressure via a dense sensory plexus.Similar mechano-transduction pathways, employ urothelial neurotransmitters to coordinate outlet resistance and afferent signalling as rapid adaptation measure to bladder filling.Peripheral neural control, including parasympathetic (pelvic), sympathetic (hypogastric) and somatic (pudendal) pathways, coordinate detrusor contraction and sphincter relaxation during micturition cycle.Spinal and supraspinal centres, integrate afferent input with higherorder modulation of LUT behaviour.The aim of our narrative review is to summarize the current knowledge on the LUT signalling pathways in health involving both the bladder and J o u r n a l P r e -p r o o f Journal Pre-proof the urethra, and highlight the integrative neurochemical pathways as future research targets for the management of different urinary disorders.