Abstract
Transient Receptor Potential (TRP) channels form a superfamily of channels that play a crucial role in the physiology of mammalian cells. However, there is very little knowledge regarding the fundamentals of intracellular trafficking of TRP channels. Here, with the help of Total Internal Reflection Fluorescence Microscopy (TIRFM), electrophysiology, calcium imaging and in vivo study - we deciphered the molecular determinants of intracellular trafficking and plasma membrane expression of TRPM8, a cold activated cation channel. Our in vitro studies revealed that TRPM8 is present in microtubule dependent dynamic intracellular structures, which also contain Lysosomal-associated membrane protein 1 (LAMP1) and Vesicle-associated membrane protein 7 (VAMP7). Furthermore, VAMP7 helps in cell surface expression of TRPM8, where TRPM8 undergoes ´kiss and linger' type fusion. Finally, sensory neurons from VAMP7-/- mice show strongly reduced TRPM8 activity, which is paralleled by a reduced avoidance of cool temperatures by VAMP7-/- mice in in vivo thermal preference tests. In conclusion, we found that TRPM8 is transported via LAMP1- and VAMP7-containing intracellular structures, where VAMP7 mediates the plasma membrane fusion of TRPM8 containing vesicles.
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