Trafficking of ThermoTRP Channels

Abstract

ThermoTRP channels (thermoTRPs) define a subfamily of the transient receptor potential (TRP) channels that are activated by changes in the environmental temperature, from noxious cold to injurious heat. Acting as integrators of several stimuli and signalling pathways, dysfunction of these channels contributes to several pathological states. The surface expression of thermoTRPs is controlled by both, the constitutive and regulated vesicular trafficking. Modulation of receptor surface density during pathological processes is nowadays considered as an interesting therapeutic approach for management of diseases, such as chronic pain, in which an increased trafficking is associated with the pathological state. This review will focus on the recent advances trafficking of the thermoTRP channels, TRPV1, TRPV2, TRPV4, TRPM3, TRPM8 and TRPA1, into/from the plasma membrane. Particularly, regulated membrane insertion of thermoTRPs channels contributes to a fine tuning of final channel activity, and indeed, it has resulted in the development of novel therapeutic approaches with successful clinical results such as disruption of SNARE-dependent exocytosis by botulinum toxin or botulinomimetic peptides.

Figure 1

Thermotransient receptor potential (TRP) channels. Structurally thermoTRP are tetramers and each subunit contains six transmembrane domains (S1–S6), a hydrophobic pore loop linking transmembrane S5 and S6, and large cytoplasmic N- and C-terminals (NB not drawn to scale). All thermoTRPs have a variable number of ankyrin repeat domains in the N-terminus, except TRPM8 which has none and instead contains TRPM homology region. ThermoTRPs display distinct thermal thresholds from very noxious cold (TRPA1) to harmful hot (TRPV2). Each thermoTRP is also activated by specific natural or synthetic compounds, known to induce the relevant thermal and pain sensations in humans. Adapted from [10].

Figure 2

Trafficking pathways of ThermoTRP channels to the plasma membrane. A neuron is illustrated here as example. (Left side). Regulated vesicles such as synaptic vesicles, filled with neurotransmitters, or secretory vesicles such as large dense core vesicles, that contain neuropeptides, can also store thermoTRP channels which are delivered to the cell surface upon stimulation by secretagogues. Docking, priming and fusion of these vesicles into the plasma membrane is a SNARE-complex and Ca²⁺-dependent process. (Right side). In the constitutive pathway, thermoTRP channels reach plasma membrane by a constant exocytosis from the trans-Golgi directly or via early endosomes (EE). Membrane levels of thermoTRP channels can be also regulated through the classic clathrin-dependent endocytosis pathway, in which dynamin form a ring around the neck of clathrin-coated pit, leading to formation of clathrin-coated vesicles which transport membrane proteins to EE. Once there, proteins could be sorted either into late endosomes and lysosomes or recycled to cell surface via recycling endosomes. ThermoTRP channels destined to degradation could be sorted into intraluminal vesicles of a multi vesicular body (MVB) and lead to lysosome or could be ubiquitinated and lead to proteasome.