Structurally, mammalian TRPV2 consists of a 6 transmembrane (TM)-domain structure flanked by a large cytosolic N- and C- terminus with a pore-forming loop between the fifth and sixth TM domains ( Huynh et al., 2016). TRPV2 is a well-conserved channel protein expressed in almost all tissues, such as the central and peripheral nervous systems, the immune system, and the muscular system. TRPV2 is a Ca 2+-permeable and polymodal channel modulated by mechanical stretch, heat, osmotic swelling, and endogenous and exogenous chemical modulators such as 2-aminoethoxydiphenyl borate (2-APB), cannabinoids, probenecid, amiloride and SKF96365 ( Bang et al., 2007 Colton and Zhu, 2007 Juvin et al., 2007 Qin et al., 2008). It has been proposed to mediate responses to noxious thermal (52☌) stimuli in medium- to large-diameter sensory neurons ( Caterina et al., 1999). Transient receptor potential vanilloid type 2 (TRPV2) was firstly identified in 1999. Our findings therefore demonstrate that flotillin-1 is a key element in TRPV2 signaling complex and modulates its cellular response.
Using site-specific mapping, we also uncovered that the SPFH (stomatin, prohibitin, flotillin, and HflK/C) domain of flotillin-1 interacted with TRPV2 N-termini and transmembrane domains 1–4, respectively. The presence of flotillin-1 enhanced the whole-cell current density of TRPV2 via increasing its surface expression levels. Fluorescent imaging and bimolecular fluorescence complementation (BiFC) further revealed that flotillin-1 and TRPV2 formed a functional complex on the cell membrane. The interaction between TRPV2 and flotillin-1 was validated through co-immuoprecipitation in situ using endogenous DRG neurons and the recombinant expression model in HEK 293T cells.
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Here by yeast two-hybrid screening of a cDNA library of mouse dorsal root ganglia (DRG) and patch clamp electrophysiology, we identified that flotillin-1, the lipid raft-associated protein, interacts with TRPV2 channel and regulates its function. The activity of TRPV2 is regulated by the molecular interactions in the subplasmalemmel signaling complex. Transient receptor potential vanilloid subtype 2 (TRPV2) channel is a polymodal receptor regulating neuronal development, cardiac function, immunity and oncogenesis.
Juan Hu 1†, Yue Gao 1†, Qian Huang 1†, Yuanyuan Wang 1, Xiaoyi Mo 1, Peiyu Wang 1, Youjing Zhang 1, Chang Xie 1, Dongdong Li 2 and Jing Yao 1*
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