The transient receptor potential family of ion channels

Abstract

The transient receptor potential (TRP) multigene superfamily encodes integral membrane proteins that function as ion channels. Members of this family are conserved in yeast, invertebrates and vertebrates. The TRP family is subdivided into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin) and TRPN (NOMPC-like); the latter is found only in invertebrates and fish. TRP ion channels are widely expressed in many different tissues and cell types, where they are involved in diverse physiological processes, such as sensation of different stimuli or ion homeostasis. Most TRPs are non-selective cation channels, only few are highly Ca2+ selective, some are even permeable for highly hydrated Mg2+ ions. This channel family shows a variety of gating mechanisms, with modes of activation ranging from ligand binding, voltage and changes in temperature to covalent modifications of nucleophilic residues. Activated TRP channels cause depolarization of the cellular membrane, which in turn activates voltage-dependent ion channels, resulting in a change of intracellular Ca2+ concentration; they serve as gatekeeper for transcellular transport of several cations (such as Ca2+ and Mg2+), and are required for the function of intracellular organelles (such as endosomes and lysosomes). Because of their function as intracellular Ca2+ release channels, they have an important regulatory role in cellular organelles. Mutations in several TRP genes have been implicated in diverse pathological states, including neurodegenerative disorders, skeletal dysplasia, kidney disorders and pain, and ongoing research may help find new therapies for treatments of related diseases.

Figure 1

A phylogenetic tree of human TRP channels. Sequence homology analyses show that all TRP channels fall into seven subfamilies that comprise proteins with distinct channel properties. Because TRPC2 is a pseudogene in human and TRPNs are not present in mammals, we used mouse TRPC2 (ENSMUSP00000102562) and fish TRPN1 (ENSDARP00000093955) to show relations between all subfamilies. Protein sequences were aligned using ClustalW2 at the EMBL-EBI server. Phylogenetic distances were calculated using PAM matrix and the unrooted tree was obtained using NJplot [102]. The TRP subfamilies are represented by different colors. The scale bar represents 0.2 substitutions. Ensembl protein IDs for human protein sequences used in the analysis are as follows: TRPM1, ENSP00000380897; TRPM2, ENSP00000381023; TRPM3, ENSP00000350140; TRPM4, ENSP00000252826; TRPM5, ENSP00000387965; TRPM6, ENSP00000354006; TRPM7, ENSP00000320239; TRPM8, ENSP00000323926; TRPV1, ENSP00000174621; TRPV2, ENSP00000342222; TRPV3, ENSP00000301365; TRPV4, ENSP00000261740; TRPV5, ENSP00000265310; TRPV6, ENSP00000352358; TRPC1, ENSP00000273482; TRPC3, ENSP00000368966; TRPC4, ENSP00000369003; TRPC5, ENSP00000262839; TRPC6, ENSP00000340913; TRPC7, ENSP00000426070; TRPML1, ENSP00000264079; TRPML2, ENSP00000359640; TRPML3, ENSP00000304843; TRPP2, ENSP00000237596; TRPP3, ENSP00000325296; TRPP5, ENSP00000290431; TRPA1, ENSP00000262209.

Figure 2

Predicted structural topology of TRP channels. (a) All channels contain six transmembrane segments (S1 to S6) with a putative pore region (P) between S5 and S6. Amino and carboxyl termini are variable in length and contain different sets of domains. (b) Distribution of domains in selected human TRP channels [103]. The number and composition of domains vary between different TRP channels and are only partially preserved within members of the same subfamily. aa, amino acids; CaM, calmodulin; EF hand, helix-loop-helix Ca²⁺ binding motif; PH, pleckstrin homology domain; ER, endoplasmic reticulum; NUDIX domain, nucleoside diphosphate linked moiety X-type motif.