Targeting TRP Channels – Valuable Alternatives to Combat Pain, Lower Urinary Tract Disorders, and Type 2 Diabetes?

Transient receptor potential (TRP) channels are a family of functionally diverse and widely expressed cation channels involved in a variety of cell signaling and sensory pathways. Research in the last two decades has not only shed light on the physiological roles of the 28 mammalian TRP channels, but also revealed the involvement of specific TRP channels in a plethora of inherited and acquired human diseases. Considering the historical successes of other types of ion channels as therapeutic drug targets, small molecules that target specific TRP channels hold promise as treatments for a variety of human conditions. In recent research, important new findings have highlighted the central role of TRP channels in chronic pain, lower urinary tract disorders, and type 2 diabetes, conditions with an unmet medical need. Here, we discuss how these advances support the development of TRP-channel-based pharmacotherapies as valuable alternatives to the current mainstays of treatment. TRP channel dysfunction is associated with a number of acquired and inherited pathologies, fueling research into specific TRP channel modulating drugs to treat a variety of human disease conditions.Specific indications include chronic pain, lower urinary tract disorders, and type 2 diabetes, global health problems for which the current mainstays of treatment are unsatisfactory.Small-molecular inhibitors of TRPV1 showed efficacy in various preclinical models of inflammatory and neuropathic pain, but the clinical development of first generation TRPV1 antagonists was halted due to dangerous on-target side effects.More tailored approaches to silence TRPV1-positive nociceptors or block specific modalities of TRPV1 activation still have potential as novel analgesic treatments.Drug development efforts are also ongoing for other TRP channels expressed in sensory neurons, in particular TRPA1, TRPM8, and TRPM3, for treatment of conditions including inflammatory and neuropathic pain as well as migraine.TRPV4, expressed in urothelial cells, is involved in sensing the fullness of the bladder; its pharmacological modulation improves bladder function in models of overactive and underactive bladder.TRPM5 plays a dual role in glucose sensing: as a transduction channel for sweet taste in the tongue, and as positive regulator of glucose-dependent electrical activity and insulin release in the pancreas. Pharmacological enhancement of TRPM5 activity represents a promising route to improve glucose homeostasis i