Transient Receptor Potential Channels and Calcium Signaling

Abstract

Transient receptor potential (TRP) cation channels play diverse roles in cellular Ca²⁺ signaling. First, as Ca²⁺-permeable channels that respond to a variety of stimuli, TRP channels can directly initiate cellular Ca²⁺ signals. Second, as nonselective cation channels, TRP channel activation leads to membrane depolarization, influencing Ca²⁺ influx via voltage-gated and store-operated Ca²⁺ channels. Finally, Ca²⁺ modulates the activity of most TRP channels, allowing them to function as molecular effectors downstream of intracellular Ca²⁺ signals. Whereas the TRP channel field has long been devoid of detailed channel structures, recent advances, particularly in cryo-electron microscopy-based structural approaches, have yielded a flurry of TRP channel structures, including members from all seven subfamilies. These structures, in conjunction with mutagenesis-based functional approaches, provided important new insights into the mechanisms whereby TRP channels permeate and sense Ca²⁺ These insights will be highly instrumental in the rational design of novel treatments for the multitude of TRP channel-related diseases.

Figure 1.

Ca²⁺ permeability of transient receptor potential (TRP) channels. On a logarithmic scale, these are examples of the indicated mammalian TRP channels illustrating the range of relative Ca²⁺ permeabilities (based on reversal potential measurements). Note that values are indicative, as the obtained values can vary significantly depending on cellular environment and experimental conditions.

Figure 2.

Cartoon illustrating three general mechanisms of Ca²⁺-dependent regulation of transient receptor potential (TRP) channel activity. (Left) Ca²⁺ (red spheres) can cause a decrease in the plasma membrane PIP₂ levels via Ca²⁺-activated phospholipase C. This decrease is sensed by PIP₂-binding domains (PBDs, purple), which are found at various locations in the cytosolic part of TRP channels. (Center) Ca²⁺ can bind directly to activate TRP channels, for instance, via residues in the S2-S3 region of TRPM channels. (Right) Ca²⁺ can influence TRP channel activity via calmodulin (CaM, blue), for example, via Ca²⁺-CaM binding in the carboxyl terminus of TRPV channels.

Figure 3.

Cladogram of mammalian transient receptor potential (TRP) channel subfamilies and their structures. A representative structure of a member of each subfamily is illustrated: hTRML1 (PDB ID: 5WJ9), hTRPP2 (5K47), hTRPA1 (3J9P), rTRPV1 (3J5P), hTRPM4 (6BQR), and hTRPC3 (6CUD). Specific domains are indicated with the following color code: pink = transmembrane domains (S1–S6), light blue = pore region, dark blue = selectivity filter, orange = ankyrin repeat domain, dark green = TRP domain, yellow = TRP box, and lime = S1–S2 extracellular domain (luminal domain [TRPML] and polycystin domain [TRPP]).

Figure 4.

Structure of transient receptor potential (TRP) channel pores. Comparison of the pore domains of TRPM4 (left, Ca²⁺-impermeable), TRPV1 (middle, Ca²⁺-permeable, nonselective), and TRPV6 (right, Ca²⁺selective). Structures are created from data in Winkler et al. (2017) (TRPM4), Liao et al. (2013) (TRPV1-apo state), and Hughes et al. (2018a) (TRPV6) (see text for more details).

Figure 5.

Structural elements underlying Ca²⁺-dependent regulation of transient receptor potential (TRP) channels. (Left) Interaction between phosphatidylinositol bisphosphate (PIP₂) and the PIP₂-binding pocket in TRPV5, which is formed by residues from the amino terminus (Arg302, Arg305), the S4–S5 linker (Lys484), and the S6-helix (Arg584). PIP₂ is shown in red, interacting amino acids in salmon. (Center) A Ca²⁺ ion (red) interacting with TRPM4 via residues Glu828, Gln831 (from S2), and Asn865 and Asp868 (from S3). (Right) Ca²⁺ ions (red) bound to calmodulin (pink), interacting with the carboxyl terminus of TRPV5 via an interaction with His699, Trp702, and Thr709 (salmon).