3sui Citations

Distinct properties of Ca2+-calmodulin binding to N- and C-terminal regulatory regions of the TRPV1 channel.

OpenAccess logo J. Gen. Physiol. 140 541-55 (2012)
Cited: 37 times
EuropePMC logo PMID: 23109716


Transient receptor potential (TRP) vanilloid 1 (TRPV1) is a molecular pain receptor belonging to the TRP superfamily of nonselective cation channels. As a polymodal receptor, TRPV1 responds to heat and a wide range of chemical stimuli. The influx of calcium after channel activation serves as a negative feedback mechanism leading to TRPV1 desensitization. The cellular calcium sensor calmodulin (CaM) likely participates in the desensitization of TRPV1. Two CaM-binding sites are identified in TRPV1: the N-terminal ankyrin repeat domain (ARD) and a short distal C-terminal (CT) segment. Here, we present the crystal structure of calcium-bound CaM (Ca(2+)-CaM) in complex with the TRPV1-CT segment, determined to 1.95-Å resolution. The two lobes of Ca(2+)-CaM wrap around a helical TRPV1-CT segment in an antiparallel orientation, and two hydrophobic anchors, W787 and L796, contact the C-lobe and N-lobe of Ca(2+)-CaM, respectively. This structure is similar to canonical Ca(2+)-CaM-peptide complexes, although TRPV1 contains no classical CaM recognition sequence motif. Using structural and mutational studies, we established the TRPV1 C terminus as a high affinity Ca(2+)-CaM-binding site in both the isolated TRPV1 C terminus and in full-length TRPV1. Although a ternary complex of CaM, TRPV1-ARD, and TRPV1-CT had previously been postulated, we found no biochemical evidence of such a complex. In electrophysiology studies, mutation of the Ca(2+)-CaM-binding site on TRPV1-ARD abolished desensitization in response to repeated application of capsaicin, whereas mutation of the Ca(2+)-CaM-binding site in TRPV1-CT led to a more subtle phenotype of slowed and reduced TRPV1 desensitization. In summary, our results show that the TRPV1-ARD is an important mediator of TRPV1 desensitization, whereas TRPV1-CT has higher affinity for CaM and is likely involved in separate regulatory mechanisms.

Reviews - 3sui mentioned but not cited (2)

  1. Structural biology of TRP channels. Hellmich UA, Gaudet R. Handb Exp Pharmacol 223 963-990 (2014)
  2. Structure of thermally activated TRP channels. Cohen MR, Moiseenkova-Bell VY. Curr Top Membr 74 181-211 (2014)

Articles - 3sui mentioned but not cited (3)

  1. Three-dimensional electron crystallography of protein microcrystals. Shi D, Nannenga BL, Iadanza MG, Gonen T. Elife 2 e01345 (2013)
  2. Distinct properties of Ca2+-calmodulin binding to N- and C-terminal regulatory regions of the TRPV1 channel. Lau SY, Procko E, Gaudet R. J. Gen. Physiol. 140 541-555 (2012)
  3. TRPM6 N-Terminal CaM- and S100A1-Binding Domains. Zouharova M, Herman P, Hofbauerová K, Vondrasek J, Bousova K. Int J Mol Sci 20 (2019)

Reviews citing this publication (14)

  1. Ca2+ Regulation of TRP Ion Channels. Hasan R, Zhang X. Int J Mol Sci 19 (2018)
  2. Dawning of a new era in TRP channel structural biology by cryo-electron microscopy. Madej MG, Ziegler CM. Pflugers Arch. 470 213-225 (2018)
  3. Understand spiciness: mechanism of TRPV1 channel activation by capsaicin. Yang F, Zheng J. Protein Cell 8 169-177 (2017)
  4. Versatile Roles of Intracellularly Located TRPV1 Channel. Zhao R, Tsang SY. J. Cell. Physiol. 232 1957-1965 (2017)
  5. TRPV1: A Target for Rational Drug Design. Carnevale V, Rohacs T. Pharmaceuticals (Basel) 9 (2016)
  6. Functional diversity and evolutionary dynamics of thermoTRP channels. Saito S, Tominaga M. Cell Calcium 57 214-221 (2015)
  7. How the TRPA1 receptor transmits painful stimuli: Inner workings revealed by electron cryomicroscopy. Brewster MS, Gaudet R. Bioessays 37 1184-1192 (2015)
  8. Application of amphipols for structure-functional analysis of TRP channels. Huynh KW, Cohen MR, Moiseenkova-Bell VY. J. Membr. Biol. 247 843-851 (2014)
  9. Calcium-permeable ion channels in pain signaling. Bourinet E, Altier C, Hildebrand ME, Trang T, Salter MW, Zamponi GW. Physiol. Rev. 94 81-140 (2014)
  10. High-resolution views of TRPV1 and their implications for the TRP channel superfamily. Hellmich UA, Gaudet R. Handb Exp Pharmacol 223 991-1004 (2014)
  11. Signal transduction: From the atomic age to the post-genomic era. Thorner J, Hunter T, Cantley LC, Sever R. Cold Spring Harb Perspect Biol 6 a022913 (2014)
  12. The ever changing moods of calmodulin: how structural plasticity entails transductional adaptability. Villarroel A, Taglialatela M, Bernardo-Seisdedos G, Alaimo A, Agirre J, Alberdi A, Gomis-Perez C, Soldovieri MV, Ambrosino P, Malo C, Areso P. J. Mol. Biol. 426 2717-2735 (2014)
  13. Structural diversity of calmodulin binding to its target sites. Tidow H, Nissen P. FEBS J. 280 5551-5565 (2013)
  14. TRP channels and pain. Julius D. Annu. Rev. Cell Dev. Biol. 29 355-384 (2013)

Articles citing this publication (18)

  1. Structural insight into the assembly of TRPV channels. Huynh KW, Cohen MR, Chakrapani S, Holdaway HA, Stewart PL, Moiseenkova-Bell VY. Structure 22 260-268 (2014)
  2. Carboxyl-terminal domain of transient receptor potential vanilloid 1 contains distinct segments differentially involved in capsaicin- and heat-induced desensitization. Joseph J, Wang S, Lee J, Ro JY, Chung MK. J. Biol. Chem. 288 35690-35702 (2013)
  3. Divalent cations potentiate TRPV1 channel by lowering the heat activation threshold. Cao X, Ma L, Yang F, Wang K, Zheng J. J. Gen. Physiol. 143 75-90 (2014)
  4. A channelopathy mechanism revealed by direct calmodulin activation of TrpV4. Loukin SH, Teng J, Kung C. Proc. Natl. Acad. Sci. U.S.A. 112 9400-9405 (2015)
  5. Adenosine triphosphate regulates the activity of guinea pig Cav1.2 channel by direct binding to the channel in a dose-dependent manner. Feng R, Xu J, Minobe E, Kameyama A, Yang L, Yu L, Hao L, Kameyama M. Am. J. Physiol., Cell Physiol. 306 C856-63 (2014)
  6. TRPA1 Channels Modify TRPV1-Mediated Current Responses in Dorsal Root Ganglion Neurons. Masuoka T, Kudo M, Yamashita Y, Yoshida J, Imaizumi N, Muramatsu I, Nishio M, Ishibashi T. Front Physiol 8 272 (2017)
  7. Conformational ensemble of the human TRPV3 ion channel. Zubcevic L, Herzik MA, Wu M, Borschel WF, Hirschi M, Song AS, Lander GC, Lee SY. Nat Commun 9 4773 (2018)
  8. Exploring functional roles of TRPV1 intracellular domains with unstructured peptide-insertion screening. Ma L, Yang F, Vu S, Zheng J. Sci Rep 6 33827 (2016)
  9. A rendezvous with the queen of ion channels: Three decades of ion channel research by David T Yue and his Calcium Signals Laboratory. Dick IE, Limpitikul WB, Niu J, Banerjee R, Issa JB, Ben-Johny M, Adams PJ, Kang PW, Lee SR, Sang L, Yang W, Babich J, Zhang M, Bazazzi H, Yue NC, Tomaselli GF. Channels (Austin) 10 20-32 (2016)
  10. Letter Competitive inhibition of TRPV1-calmodulin interaction by vanilloids. Hetényi A, Németh L, Wéber E, Szakonyi G, Winter Z, Jósvay K, Bartus É, Oláh Z, Martinek TA. FEBS Lett. 590 2768-2775 (2016)
  11. De Novo Modular Development of a Foldameric Protein-Protein Interaction Inhibitor for Separate Hot Spots: A Dynamic Covalent Assembly Approach. Bartus É, Hegedüs Z, Wéber E, Csipak B, Szakonyi G, Martinek TA. ChemistryOpen 6 236-241 (2017)
  12. Full-Spectral Multiplexing of Bioluminescence Resonance Energy Transfer in Three TRPV Channels. Ruigrok HJ, Shahid G, Goudeau B, Poulletier de Gannes F, Poque-Haro E, Hurtier A, Lagroye I, Vacher P, Arbault S, Sojic N, Veyret B, Percherancier Y. Biophys. J. 112 87-98 (2017)
  13. Mechanism of calmodulin inactivation of the calcium-selective TRP channel TRPV6. Singh AK, McGoldrick LL, Twomey EC, Sobolevsky AI. Sci Adv 4 eaau6088 (2018)
  14. Shared CaM- and S100A1-binding epitopes in the distal TRPM4 N terminus. Bousova K, Herman P, Vecer J, Bednarova L, Monincova L, Majer P, Vyklicky L, Vondrasek J, Teisinger J. FEBS J. 285 599-613 (2018)
  15. Molecular basis for heat desensitization of TRPV1 ion channels. Luo L, Wang Y, Li B, Xu L, Kamau PM, Zheng J, Yang F, Yang S, Lai R. Nat Commun 10 2134 (2019)
  16. Recognition of 2',5'-linked oligoadenylates by human ribonuclease L: molecular dynamics study. Maláč K, Barvík I. J Mol Model 20 2123 (2014)
  17. Structural Basis of TRPV4 N Terminus Interaction with Syndapin/PACSIN1-3 and PIP2. Goretzki B, Glogowski NA, Diehl E, Duchardt-Ferner E, Hacker C, Gaudet R, Hellmich UA. Structure 26 1583-1593.e5 (2018)
  18. The role of calmodulin in regulating calcium-permeable PKD2L1 channel activity. Park EYJ, Baik JY, Kwak M, So I. Korean J. Physiol. Pharmacol. 23 219-227 (2019)