What do we know about the transient receptor potential vanilloid 2 (TRPV2) ion channel?

Abstract

Transient receptor potential (TRP) ion channels are emerging as a new set of membrane proteins involved in a vast array of cellular processes and regulated by a large number of physical and chemical stimuli, which involves them with sensory cell physiology. The vanilloid TRP subfamily (TRPV) named after the vanilloid receptor 1 (TRPV1) consists of six members, and at least four of them (TRPV1-TRPV4) have been related to thermal sensation. One of the least characterized members of the TRP subfamily is TRPV2. Although initially characterized as a noxious heat sensor, TRPV2 now seems to have little to do with temperature sensing but a much more complex physiological profile. Here we review the available information and research progress on the structure, physiology and pharmacology of TRPV2 in an attempt to shed some light on the physiological and pharmacological deorphanization of TRPV2.

Keywords: TRPV2; calcium signalling; cancer; endocrinology; immunology; ion channels; muscle physiology; neuroscience; pharmacology; somatosensation.

Fig. 1. The TRP channels molecular mechanism and classification

A. The six transmembrane segment topology of the monomer and tetrameric functional unit of TRP channels. The cytoplasmic N- and C-terminal domains, and the transmembrane domain constituting the pore are indicated. The long loop present between S1 and S2 in TRPP and TRPML is indicated by a dashed line. The transmembrane domain comprises segments 1 to 4 (red), distal to the pore, and the segments 5 and 6 (blue) proximal to the pore of the channel. B. Human classification of the TRP family representative of the mammal TRP subfamilies classification. Notice that in humans, TRPC2 is a non-coding pseudogene and it is not represented.

Fig. 2. TRPV2 sequence conservation and structural features

Alignment of rat (rTRPV2), mouse (mTRPV2), and human (hTRPV2) orthologs. The most relevant sequence features are indicated using the following color code: ARD (light blue); S1–S4 (red); S5–S6 (dark blue); pore (violet); selectivity filter (magenta); PIP₂ binding domain (yellow); Calmodulin binding domain (orange); TRP box (black). The N-glycosylation sites between S5 and S6 are indicated by black arrows. For details see the text. The alignment consensus indicates the conservation degree obtained by aligning the following UNIPROT codes: Q9WUD2, Q9WTR1, Q9Y5S, E2RLX8, F6WJB2, F7BDA4, F7A622, G1RXC4, G1SNM3, F1SDE4, G3T6Z2, G3GVL1, Q5EA32, G3WJU0, F6RMV4, F7A8J8, G1N455, F1NPJ9, F6UY90. The alignment has been built in MAFFT [136] and plotted using JalView [137] and the functional ZAPPO profile. Inset, the human TRPV1-4 pore region aligned highlighting the differences in respect to the pore and selectivity filter consensus sequence.

Fig 3. The TRPV2-ARD concave surface has a small conserved region

The sequence conservation of TRPV1 and TRPV2 orthologues is mapped onto the crystal structures of the TRPV1-ARD (left, [70]) and TRPV2-ARD (right, [42]), respectively, using ConSurf [138]. The degree of conservation follows a gradient from magenta, most conserved, to cyan, least conserved. The ATP binding region in TRPV1-ARD is indicated by a dashed outline.