Structural mechanisms of transient receptor potential ion channels

Abstract

Transient receptor potential (TRP) ion channels are evolutionarily ancient sensory proteins that detect and integrate a wide range of physical and chemical stimuli. TRP channels are fundamental for numerous biological processes and are therefore associated with a multitude of inherited and acquired human disorders. In contrast to many other major ion channel families, high-resolution structures of TRP channels were not available before 2013. Remarkably, however, the subsequent “resolution revolution” in cryo-EM has led to an explosion of TRP structures in the last few years. These structures have confirmed that TRP channels assemble as tetramers and resemble voltage-gated ion channels in their overall architecture. But beyond the relatively conserved transmembrane core embedded within the lipid bilayer, each TRP subtype appears to be endowed with a unique set of soluble domains that may confer diverse regulatory mechanisms. Importantly, TRP channel structures have revealed sites and mechanisms of action of numerous synthetic and natural compounds, as well as those for endogenous ligands such as lipids, Ca2+, and calmodulin. Here, I discuss these recent findings with a particular focus on the conserved transmembrane region and how these structures may help to rationally target this important class of ion channels for the treatment of numerous human conditions.

Steroids and TRP Channels: A Close Relationship

“…The recently obtained high-resolution structures for several of these channels have shown that they are formed by four subunits (tetramer) [5,6], Figure 1, where each monomer is a six-pass transmembrane protein (S1-S6), with the N-and C-terminus intracellularly localized [6]subunits contain a re-entrant loop located between S5-S6, forming the pore or ion conduction pathway. Some of these channels contain ankyrin repeat domains (ARDs) in the N-terminus and a TRP-domain (a highly conserved 25-amino-acid α-helix structure parallel to the inner plasma membrane) at the C-terminus [5,6], Figure 2. The recently obtained high-resolution structures for several of these channels have shown that they are formed by four subunits (tetramer) [5,6], Figure 1, where each monomer is a six-pass transmembrane protein (S1-S6), with the N-and C-terminus intracellularly localized [6].…”

“…Some of these channels contain ankyrin repeat domains (ARDs) in the N-terminus and a TRP-domain (a highly conserved 25-amino-acid α-helix structure parallel to the inner plasma membrane) at the C-terminus [5,6], Figure 2. The recently obtained high-resolution structures for several of these channels have shown that they are formed by four subunits (tetramer) [5,6], Figure 1, where each monomer is a six-pass transmembrane protein (S1-S6), with the N-and C-terminus intracellularly localized [6]. The subunits contain a re-entrant loop located between S5-S6, forming the pore or ion conduction pathway.…”

“…The subunits contain a re-entrant loop located between S5-S6, forming the pore or ion conduction pathway. Some of these channels contain ankyrin repeat domains (ARDs) in the N-terminus and a TRP-domain (a highly conserved 25-amino-acid α-helix structure parallel to the inner plasma membrane) at the C-terminus [5,6], Figure 2. Structurally TRP channels are formed by six transmembrane domains (S1-S6) with the pore loop between S5 and S6; four identical subunits form a functional channel.…”

“…The recently obtained high-resolution structures for several of these channels have shown that they are formed by four subunits (tetramer) [ 5 , 6 ], Figure 1 , where each monomer is a six-pass transmembrane protein (S1–S6), with the N- and C-terminus intracellularly localized [ 6 ]. The subunits contain a re-entrant loop located between S5–S6, forming the pore or ion conduction pathway.…”

TRP Channels Role in Pain Associated With Neurodegenerative Diseases

“…TRPV channels are activated by chemical ligands, such as capsaicin or cannabinoids, but also by noxious heat (>43 • C), low pH (<6) (Caterina et al, 1997;Tominaga et al, 1998) and voltage changes inducing depolarization (Cao, 2020). TRPVs are also activated by lipid signaling (Cortright and Szallasi, 2004;Jung et al, 2004), and eicosanoids, signaling molecules produced by the enzymatic or non-enzymatic oxidation of arachidonic acid or other similar polyunsaturated fatty acids (Hwang et al, 2000).…”