Interaction between TRP and Ca2+-activated chloride channels

The transient receptor potential (TRP) channel superfamily includes a large number of proteins that constitute 7 subfamilies (TRPC, TRPV, TRPM, TRPML, TRPN, TRPA and TRPP). These channels have been strongly conserved evolutionarily. The family was first cloned from a mutant Drosophila strain in which receptor potentials in the eye were transient upon light stimulation. There are 27 known channels in the 6 subfamilies, excluding TRPN in humans. Some of the TRP channels respond to a wide variety of sensory stimuli, including chemicals and temperature changes. Thus, they are termed “thermosensitive” TRP channels. Three in particular (TRPV1, a capsaicin receptor, TRPA1, a receptor for mustard oil, and TRPM8, a menthol receptor) are involved in temperature sensation in sensory neurons. The structure of TRPV1 was recently solved at a 3.4 Å level using a single particle analysis with cryo-electron microscopy. One of the key characteristics of thermosensitive TRP channels is their high Ca permeability that is more than 5 times larger than that of sodium. Therefore, thermosensitive TRP channels might well play important roles involving Ca. There are many Ca binding proteins in the cytosol that contribute to tight regulation of intracellular Ca concentrations. Nonetheless, upon entering the cells through TRP channels, Ca is certainly involved in mediating various intracellular events. Indeed, TRPV4, a thermosensitive TRP channel (reportedly an osmoor mechano-sensor, and anoctamin 1 (TMEM16A; a Caactivated chloride channel), functionally interact in choroid plexus epithelial cells in the brain. Upon entering choroid plexus epithelial cells, Ca activates anoctamin 1, leading to chloride efflux because the chloride equilibrium potential in choroid plexus epithelial cells is smaller than the resting membrane potentials due to relatively high intracellular chloride concentrations. The chloride efflux could drive water movement from the choroid plexus epithelial cells to ventricles, a process that could be viewed as a mechanism for release of cerebrospinal fluid from the choroid plexus. Aquaporin (AQP) 1 and AQP4 water channels are well-expressed in choroid plexus epithelial cells, and TRPV4 directly interacts with AQP4. Activation of anoctamin 1 was also observed downstream of Gq-coupled receptor activation that can increase intracellular Ca concentrations though Ca release from intracellular Ca stores by Ins(1,4,5) P 3 receptor activation. However, activation of anoctamin 1 was not frequently observed following a simple increase in intracellular Ca concentration compared with that seen after TRP channel activation. This result indicated that Ca entering the cells through Ca-permeable channels activated anoctamin 1 more effectively. In fact, co-immunoprecipitation studies showed that TRPV4 physically interacted with anoctamin 1, suggesting that co-localization of the 2 proteins is important. The findings presented in the work illustrate the significance of TRPV4 in choroid plexus epithelial cells and emphasize the importance of the interaction between Ca-permeable channels and Ca-activated proteins Interaction between TRP and Ca-activated chloride channels