Transient Receptor Potential Channels

TRP Channel Structure and Classification

All TRP channels are homo- or heterotetramers, composed of subunits with 6 transmembrane domains, which assemble to form a central pore that is permeable to cations. Cation selectivity of TRP channels is dependent on the subfamily and subtype, however for all TRP channels activation leads for a conformation change allowing channel opening and influx of cations, which leads to membrane depolarization. The cytoplasmic tails of TRP channel subunits contain various structural and functional domains, dependent on the TRP channel subfamily. These domains may include ankyrin repeats, coiled-coil domains, calmodulin and Ca²⁺ binding domains, PDZ domains, and serine/threonine kinases such as protein kinase A, protein kinase C and MAP kinases.

Unlike other ion channels, which are grouped based on a common ligand, function or ion selectivity, TRP channels are grouped into families based on sequence homology. TRPA1, TRPC, TRPM and TRPV channels have the highest homology, while TRPML and TRPP channels are more distantly related. Each family has a varying number of subtypes, with the exception of TRPA1, which is the only member of the TRPA family in mammals.

TRP Channel Activation Mechanism

TRP channels respond to various stimuli and activation methods including:

• Ligand activation - endogenous and exogenous small molecules bind and cause channel opening
• Direct activation - change in environmental stimuli, such as mechanical stress or temperature, causes a conformational change and channel opening
• Activation downstream of receptor-mediated signaling pathways - G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) activate signaling cascades that modulate TRP channel activity

It is generally accepted that all TRP channels are activated downstream of G_q-linked GPCRs, and RTKs. However, most TRP channels respond to multiple stimuli and integrate these stimuli, coupling them to downstream signaling cascades through elevation of intracellular Ca²⁺ levels and membrane depolarization. This allows cells expressing TRP channels to sense and act on changes in the local environment, including changes to temperature, fluid flow and mechanical stress, and gives roles for TRP channels in processes as varied as regulation of vascular tone, fertilization, chemotaxis and neurite outgrowth.