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Molecular Mechanism of TRP Channels

Jie Zheng

10.1002/cphy.c120001

Source: Volume 3, Issue 1, January 2013

Published online: January 2013

Full Article on Wiley Online Library



Abstract

Transient receptor potential (TRP) channels are cellular sensors for a wide spectrum of physical and chemical stimuli. They are involved in the formation of sight, hearing, touch, smell, taste, temperature, and pain sensation. TRP channels also play fundamental roles in cell signaling and allow the host cell to respond to benign or harmful environmental changes. As TRP channel activation is controlled by very diverse processes and, in many cases, exhibits complex polymodal properties, understanding how each TRP channel responds to its unique forms of activation energy is both crucial and challenging. The past two decades witnessed significant advances in understanding the molecular mechanisms that underlie TRP channels activation. This review focuses on our current understanding of the molecular determinants for TRP channel activation. © 2013 American Physiological Society. Compr Physiol 3:221‐242, 2013.

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Figure 1. Figure 1.

Transient receptor potential (TRP) channel subfamilies. The subunit topology is shown with highlights of specific functional domains. Subunits known to coassemble are indicated by lines.
Figure 2. Figure 2.

Electron microscopy (EM) structures of transient receptor potential (TRP) channels. (A) Cryo‐EM structures of TRPV1. Blue lines indicate the position of the cell membrane. (B) The crystal structures of Kv2.1 transmembrane domains (PDB 2A79) and TRPV1 ankyrin‐like repeat domains (PDB 2PNN) docked into the TRPV1 cryo‐EM structure. (C) Cryo‐EM structure of Shaker potassium channel. Adapted, with permission, from references (110,167). Scale bar for A and C, 10 nm.
Figure 3. Figure 3.

(A) Crystal structure of the TRPV2 ankyrin‐like repeat domain. (B) Comparison between TRPV2 ankyrin‐like repeat domain and the repeats 16‐21 of ankyrin (PDB 1N11). (A) and (B) are Adapted, with permission, from reference (72). (C) Crystal structures of the coiled‐coil domain of TRPM7 (left), TRPP2 (middle), and CNGA1 (right). Adapted, with permission, from references (40,227,163), respectively.
Figure 4. Figure 4.

(A) schematic drawing of the voltage‐dependent gating of the Kv channel (left) and CLC‐0 channel (right). The red + and − signs indicate positive charged amino acids and chloride ion, respectively. For the Kv channel, charges carried by arginine and lysine residues in the fourth transmembrane segment, S4, serve as the primary gating charges. Changes in transmembrane voltage drive the movement of S4, which is coupled to the opening of the activation gate. For the CLC‐0 channel, the permeant ion Cl− in the pore carries the gating charge. (B) Voltage‐dependent gating of TRPV1 and Kv channels.
Figure 5. Figure 5.

Temperature‐dependent activation of thermo TRP channels and CLC‐0 channel. The Popen‐T (top panel) and ΔG‐T (bottom panel) relationships for each channel are predicted from the measured values for enthalpic and entropic changes. Horizontal and vertical dotted lines indicate the zero ΔG level and the half‐activation temperature, respectively. Red and green traces represent the predicted Popen‐T and ΔG‐T relationships of TRPV1 when the enthalpic change is decreased or increased by 5%, respectively. The ΔG‐T relationship of heat‐sensitive channels has a negative slope; an increase in temperature causes a decrease in ΔG and a shift of the closed‐to‐open equilibrium toward the open state. In contrast, the ΔG‐T relationship of cold‐sensitive channels has a positive slope. CLC‐0 has a “normal” fast gating process and a highly temperature‐sensitive common gating process. Adapted, with permission, from reference (219).
Figure 6. Figure 6.

(Left panel) At the cellular level, heat and capsaicin share the same target (TRPV1) for activating sensory neurons, which elicits the sensation of heat or pain. (Right panel) At the molecular level, heat and capsaicin work through distinct activation pathways.
Figure 7. Figure 7.

(A) The molecular structure of vanillin, TRPV1 activator capsaicin, capsazepine (TRPV1 antagonist), and resiniferatoxin (TRPV1 agonist). (B) Dose‐response relationship for TRPV1 homomeric channel and TRPV1/TRPV3 heteromeric channel. (C) Representative single‐channel traces from TRPV1 homomeric channel (top) and TRPV1/TRPV3 heteromeric channel (bottom) in response to 10 μmol/L capsaicin. Panels B and C are Adapted, with permission, from reference (17).
Figure 8. Figure 8.

The molecular structure of the TRPM8 activator menthol, icilin, and eucalyptol.
Figure 9. Figure 9.

(A) A topology plot of TRPV1 subunit showing the major pH sites E600 and E648, and other pH sites. (B) (Left panel) A structural model of the mouse TRPV1 channel showing the location of E601 (equivalent to E600 of the rat TRPV1 channel; shown in space‐filling mode). (Right panel) Potential interaction between E601 and N626.


Figure 1.

Transient receptor potential (TRP) channel subfamilies. The subunit topology is shown with highlights of specific functional domains. Subunits known to coassemble are indicated by lines.



Figure 2.

Electron microscopy (EM) structures of transient receptor potential (TRP) channels. (A) Cryo‐EM structures of TRPV1. Blue lines indicate the position of the cell membrane. (B) The crystal structures of Kv2.1 transmembrane domains (PDB 2A79) and TRPV1 ankyrin‐like repeat domains (PDB 2PNN) docked into the TRPV1 cryo‐EM structure. (C) Cryo‐EM structure of Shaker potassium channel. Adapted, with permission, from references (110,167). Scale bar for A and C, 10 nm.



Figure 3.

(A) Crystal structure of the TRPV2 ankyrin‐like repeat domain. (B) Comparison between TRPV2 ankyrin‐like repeat domain and the repeats 16‐21 of ankyrin (PDB 1N11). (A) and (B) are Adapted, with permission, from reference (72). (C) Crystal structures of the coiled‐coil domain of TRPM7 (left), TRPP2 (middle), and CNGA1 (right). Adapted, with permission, from references (40,227,163), respectively.



Figure 4.

(A) schematic drawing of the voltage‐dependent gating of the Kv channel (left) and CLC‐0 channel (right). The red + and − signs indicate positive charged amino acids and chloride ion, respectively. For the Kv channel, charges carried by arginine and lysine residues in the fourth transmembrane segment, S4, serve as the primary gating charges. Changes in transmembrane voltage drive the movement of S4, which is coupled to the opening of the activation gate. For the CLC‐0 channel, the permeant ion Cl− in the pore carries the gating charge. (B) Voltage‐dependent gating of TRPV1 and Kv channels.



Figure 5.

Temperature‐dependent activation of thermo TRP channels and CLC‐0 channel. The Popen‐T (top panel) and ΔG‐T (bottom panel) relationships for each channel are predicted from the measured values for enthalpic and entropic changes. Horizontal and vertical dotted lines indicate the zero ΔG level and the half‐activation temperature, respectively. Red and green traces represent the predicted Popen‐T and ΔG‐T relationships of TRPV1 when the enthalpic change is decreased or increased by 5%, respectively. The ΔG‐T relationship of heat‐sensitive channels has a negative slope; an increase in temperature causes a decrease in ΔG and a shift of the closed‐to‐open equilibrium toward the open state. In contrast, the ΔG‐T relationship of cold‐sensitive channels has a positive slope. CLC‐0 has a “normal” fast gating process and a highly temperature‐sensitive common gating process. Adapted, with permission, from reference (219).



Figure 6.

(Left panel) At the cellular level, heat and capsaicin share the same target (TRPV1) for activating sensory neurons, which elicits the sensation of heat or pain. (Right panel) At the molecular level, heat and capsaicin work through distinct activation pathways.



Figure 7.

(A) The molecular structure of vanillin, TRPV1 activator capsaicin, capsazepine (TRPV1 antagonist), and resiniferatoxin (TRPV1 agonist). (B) Dose‐response relationship for TRPV1 homomeric channel and TRPV1/TRPV3 heteromeric channel. (C) Representative single‐channel traces from TRPV1 homomeric channel (top) and TRPV1/TRPV3 heteromeric channel (bottom) in response to 10 μmol/L capsaicin. Panels B and C are Adapted, with permission, from reference (17).



Figure 8.

The molecular structure of the TRPM8 activator menthol, icilin, and eucalyptol.



Figure 9.

(A) A topology plot of TRPV1 subunit showing the major pH sites E600 and E648, and other pH sites. (B) (Left panel) A structural model of the mouse TRPV1 channel showing the location of E601 (equivalent to E600 of the rat TRPV1 channel; shown in space‐filling mode). (Right panel) Potential interaction between E601 and N626.

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Further Reading
 1. Bertil Hille, Ion Channels of Excitable Membranes (3rd ed). Sunderland: Sinauer Associates, Inc., 2001.

Further Reading

Bertil Hille, Ion Channels of Excitable Membranes, 3rd edition, 2001, Sinauer Associates, Inc., Sunderland


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Article Title: Molecular Mechanism of TRP Channels
 

How to Cite

Jie Zheng. Molecular Mechanism of TRP Channels. Compr Physiol 2013, 3: 221-242. doi: 10.1002/cphy.c120001