TRP channels in lower urinary tract dysfunction

Abstract

Lower urinary tract dysfunction (LUTd) represents a major healthcare problem. Although it is mostly not lethal, associated social disturbance, medical costs, loss of productivity and especially diminished quality of life should not be underestimated. Although more than 15% of people suffer from a form of LUTd to some extent, pathophysiology often remains obscure. In the past 20 years, transient receptor potential (TRP) channels have become increasingly important in this field of research. These intriguing ion channels are believed to be the main molecular sensors that generate bladder sensation. Therefore, they are intensely pursued as new drug targets for both curative and symptomatic treatment of different forms of LUTd. TRPV1 was the first of its class to be investigated. Actually, even before this channel was cloned, it had already been targeted in the bladder, with clinical trials of intravesical capsaicin instillations. Several other polymodally gated TRP channels, particularly TRPM8, TRPA1 and TRPV4, also appear to play a prominent role in bladder (patho)physiology. With this review, we provide a brief overview of current knowledge on the role of these TRP channels in LUTd and their potential as molecular targets for treatment. LINKED ARTICLESThis article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx

DFL23448, A Novel Transient Receptor Potential Melastin 8-Selective Ion Channel Antagonist, Modifies Bladder Function and Reduces Bladder Overactivity in Awake Rats

“…The transient receptor potential ion channel (TRP) superfamily is widely expressed in mammals and consists of six subfamilies of proteins, which may be considered as polymodal cell sensors that are involved in various biologic processes and diseases (Flockerzi and Nilius, 2014). Some TRPs that are expressed in the lower urinary tract have been correlated with sensory bladder function and dysfunction and are being explored as drug targets in bladder disease (Franken et al, 2014). A subset of TRP channels may be classified as thermosensors, including transient receptor potential vanilloid 1 (TRPV1; heat), transient receptor potential melastatin 8 (TRPM8; cold), and transient receptor potential ankyrin 1 (TRPA1; moderate cold); however, these TRP channels also respond to other noxious stimuli as well as various exogenous or endogenous agents Franken et al, 2014).…”

“…Some TRPs that are expressed in the lower urinary tract have been correlated with sensory bladder function and dysfunction and are being explored as drug targets in bladder disease (Franken et al, 2014). A subset of TRP channels may be classified as thermosensors, including transient receptor potential vanilloid 1 (TRPV1; heat), transient receptor potential melastatin 8 (TRPM8; cold), and transient receptor potential ankyrin 1 (TRPA1; moderate cold); however, these TRP channels also respond to other noxious stimuli as well as various exogenous or endogenous agents Franken et al, 2014). TRPV1 is the channel best studied in the lower urinary tract, but the mechanism of action of TRPV1-active compounds is not completely established and their usefulness in lower urinary tract disorders is debated Franken et al, 2014).…”

“…A subset of TRP channels may be classified as thermosensors, including transient receptor potential vanilloid 1 (TRPV1; heat), transient receptor potential melastatin 8 (TRPM8; cold), and transient receptor potential ankyrin 1 (TRPA1; moderate cold); however, these TRP channels also respond to other noxious stimuli as well as various exogenous or endogenous agents Franken et al, 2014). TRPV1 is the channel best studied in the lower urinary tract, but the mechanism of action of TRPV1-active compounds is not completely established and their usefulness in lower urinary tract disorders is debated Franken et al, 2014). Previous studies in which TRPM8, together with TRPA1, was isolated from human prostate tissue suggest that both receptors may be involved in bladder responses to cold (Tsavaler et al, 2001;Franken et al, 2014).…”

“…TRPV1 is the channel best studied in the lower urinary tract, but the mechanism of action of TRPV1-active compounds is not completely established and their usefulness in lower urinary tract disorders is debated Franken et al, 2014). Previous studies in which TRPM8, together with TRPA1, was isolated from human prostate tissue suggest that both receptors may be involved in bladder responses to cold (Tsavaler et al, 2001;Franken et al, 2014). TRPM8 and TRPA1 are both expressed in mucosal cells and afferent nerves of the bladder and urethra, and both receptors have been implicated in bladder overactivity in experimental models or lower urinary tract symptoms in humans; however, their respective role in cold-induced bladder responses have not been clarified Franken et al, 2014).…”

“…Previous studies in which TRPM8, together with TRPA1, was isolated from human prostate tissue suggest that both receptors may be involved in bladder responses to cold (Tsavaler et al, 2001;Franken et al, 2014). TRPM8 and TRPA1 are both expressed in mucosal cells and afferent nerves of the bladder and urethra, and both receptors have been implicated in bladder overactivity in experimental models or lower urinary tract symptoms in humans; however, their respective role in cold-induced bladder responses have not been clarified Franken et al, 2014). The bladder can react to thermal cold by at least two principally different neurophysiological doctrines: 1) by local activation of thermal receptors within its sphere, such as during the controversial ice-water test, which elicits a visceral sensorimotor reflex (the bladder-cooling reflex) (Hellström et al, 1991;Drake et al, 2010;Franken et al, 2014); or 2) by activation of somatosensory pathways, which is suggested to depend on segmental dichotomizing afferent axons of the skin and viscera (Shibata et al, 2011).…”