Chapter 6 Advances in Transient Receptor Potential Modulators

Publisher Summary This chapter focuses on the modulators of the various transient receptor potential (TRP) channels and their role in understanding the function of these channels, and the potential therapeutic benefits of targeting TRP ion channels. Various receptor discussed are TRPV1 (vanilloid receptor), TRPV3, TRPV4, RPM2/TRPM5/TRPM8, and TRPA1. Among the various members of the TRP superfamily, the vanilloid-1 receptor has emerged as a particularly attractive target for the treatment of acute and chronic pain. Regarded as a polymodal molecular integrator in nociception, TRPV1 is a nonselective cation channel localized on sensory neurons in C- and Aδ-fibers in sensory ganglia. TRPV3 is activated by heat and, unlike most thermo-TRPs, is expressed in mouse keratinocytes and not in the dorsal root ganglia. TRPV3 null mice have strong deficits in response to innocuous and noxious heat but not in other sensory modalities; hence, TRPV3 has a specific role in thermosensation. TRPV4 is a mechanosensitive, nonselective cation channel that is activated under hypotonic conditions and serves as an osmoreceptor. TRPV4 is expressed in brain, liver, kidney, heart, testis, and salivary glands. TRPV4 knockout mice at eight weeks of age were normal, but those at 24 weeks revealed significantly higher thresholds of auditory brainstem response. These and other studies suggest that disruption of TRPV4 causes delayed-onset hearing loss and makes the cochlea vulnerable to acoustic injury. TRPA1 which is the sole known member of the TRPA (TRPAnkyrin) family, is a nonselective cation channel expressed in subsets of the dorsal root and trigeminal ganglia.