“…This MmTRPM8 structure largely resembles structures of other mammalian TRPM channels such as TRPM4, TRPM5, and TRPM7 (refs. 18 – 22 ). Fig.…”
Section: Resultsmentioning
confidence: 99%
“…These studies provide a glimpse of the overall architectures of TRPM8. FaTRPM8 and PmTRPM8 have two features that differ from those of other mammalian TRPM channels such as TRPM4, TRPM5, and TRPM7 whose structures have been reported 18 – 22 . First, in the ligand-free states of bird TRPM8 structures (FaTRPM8 ligand-free , PDB: 6BPQ; PmTRPM8 ligand-free , PBD: 6O6A), the linker helix (S4-S5 linker) that connects transmembrane helices S4 and S5 forms a single straight helix with S5; in addition, the pore helices are resolved in low resolution, and selectivity filters and outer pore loops are invisible, likely due to their dynamics (Supplementary Fig.…”
Transient receptor potential melastatin 8 (TRPM8) channel is a Ca2+-permeable non-selective cation channel that acts as the primary cold sensor in humans. TRPM8 is also activated by ligands such as menthol, icilin, and phosphatidylinositol 4,5-bisphosphate (PIP2), and desensitized by Ca2+. Here we have determined electron cryo-microscopy structures of mouse TRPM8 in the absence of ligand, and in the presence of Ca2+ and icilin at 2.5–3.2 Å resolution. The ligand-free state TRPM8 structure represents the full-length structure of mammalian TRPM8 channels with a canonical S4-S5 linker and the clearly resolved selectivity filter and outer pore loop. TRPM8 has a short but wide selectivity filter which may account for its permeability to hydrated Ca2+. Ca2+ and icilin bind in the cytosolic-facing cavity of the voltage-sensing-like domain of TRPM8 but induce little conformational change. All the ligand-bound TRPM8 structures adopt the same closed conformation as the ligand-free structure. This study reveals the overall architecture of mouse TRPM8 and the structural basis for its ligand recognition.
“…This MmTRPM8 structure largely resembles structures of other mammalian TRPM channels such as TRPM4, TRPM5, and TRPM7 (refs. 18 – 22 ). Fig.…”
Section: Resultsmentioning
confidence: 99%
“…These studies provide a glimpse of the overall architectures of TRPM8. FaTRPM8 and PmTRPM8 have two features that differ from those of other mammalian TRPM channels such as TRPM4, TRPM5, and TRPM7 whose structures have been reported 18 – 22 . First, in the ligand-free states of bird TRPM8 structures (FaTRPM8 ligand-free , PDB: 6BPQ; PmTRPM8 ligand-free , PBD: 6O6A), the linker helix (S4-S5 linker) that connects transmembrane helices S4 and S5 forms a single straight helix with S5; in addition, the pore helices are resolved in low resolution, and selectivity filters and outer pore loops are invisible, likely due to their dynamics (Supplementary Fig.…”
Transient receptor potential melastatin 8 (TRPM8) channel is a Ca2+-permeable non-selective cation channel that acts as the primary cold sensor in humans. TRPM8 is also activated by ligands such as menthol, icilin, and phosphatidylinositol 4,5-bisphosphate (PIP2), and desensitized by Ca2+. Here we have determined electron cryo-microscopy structures of mouse TRPM8 in the absence of ligand, and in the presence of Ca2+ and icilin at 2.5–3.2 Å resolution. The ligand-free state TRPM8 structure represents the full-length structure of mammalian TRPM8 channels with a canonical S4-S5 linker and the clearly resolved selectivity filter and outer pore loop. TRPM8 has a short but wide selectivity filter which may account for its permeability to hydrated Ca2+. Ca2+ and icilin bind in the cytosolic-facing cavity of the voltage-sensing-like domain of TRPM8 but induce little conformational change. All the ligand-bound TRPM8 structures adopt the same closed conformation as the ligand-free structure. This study reveals the overall architecture of mouse TRPM8 and the structural basis for its ligand recognition.
“…There are currently five channels in the TRPM family for which structural data are available (43): TRPM2 (44), TRPM4 (45), TRPM5 (46), TRPM7 (33) and TRPM8 (28). While all of these channels have been shown to be positively regulated by PI(4,5)P 2 (23), only TRPM8 has a co-structure with this lipid (28).…”
Transient Receptor Potential Melastatin 3 (TRPM3) is a heat-activated ion channel expressed in peripheral sensory neurons and the central nervous system. TRPM3 activity depends on the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], but the molecular mechanism of activation by PI(4,5)P2 is not known. As no experimental structure of TRPM3 is available, we built a homology model of the channel in complex with PI(4,5)P2 via molecular modeling. We identified putative contact residues for PI(4,5)P2 in the pre-S1 segment, the S4-S5 linker, and the proximal C-terminal TRP-domain. Mutating these residues increased sensitivity to inhibition of TRPM3 by decreasing PI(4,5)P2 levels by phosphatidylinositol 4-kinase inhibition. Changes in ligand-binding affinities via MM/GBSA showed reduced PI(4,5)P2 affinity for the mutants. Mutating PI(4,5)P2 interacting residues also reduced sensitivity for activation by the endogenous ligand pregnenolone sulfate (PregS), pointing to an allosteric interaction between PI(4,5)P2 and PregS. Mutating residues in the PI(4,5)P2 binding site in TRPM8 had similar effects, increased sensitivity to PI(4,5)P2 depletion, and reduced sensitivity to menthol. Mutation of most PI(4,5)P2 interacting residues in TRPM3 also increased sensitivity to inhibition by Gβγ, indicating allosteric interaction between Gβγ and PI(4,5)P2. Disease-associated gain of function TRPM3 mutations on the other hand, resulted in no change of PI(4,5)P2 sensitivity, indicating that mutations did not increase channel activity via increasing PI(4,5)P2 interactions. Our data provide insight into the mechanism of regulation of TRPM3 by PI(4,5)P2, its relationship to endogenous activators and inhibitors of TRPM3, as well as identify similarities and differences between PI(4,5)P2 regulation of TRPM3 and TRPM8.
“…However, both TRPM4 and TRPM5 have a direct Ca 2+ binding site on the intracellular side of the S1–S4 domain [ 83 ]. TRPM4, but not TRPM5, is inhibited by extracellular adenosine nucleotides (AMP, ADP, ATP) and its activity can be enhanced by PKC dependent phosphorylation of the TRP domain [ 84 ].…”
Plasma membrane protein channels provide a passageway for ions to access the intracellular milieu. Rapid entry of calcium ions into cells is controlled mostly by ion channels, while Ca2+-ATPases and Ca2+ exchangers ensure that cytosolic Ca2+ levels ([Ca2+]cyt) are maintained at low (~100 nM) concentrations. Some channels, such as the Ca2+-release-activated Ca2+ (CRAC) channels and voltage-dependent Ca2+ channels (CACNAs), are highly Ca2+-selective, while others, including the Transient Receptor Potential Melastatin (TRPM) family, have broader selectivity and are mostly permeable to monovalent and divalent cations. Activation of CRAC channels involves the coupling between ORAI1-3 channels with the endoplasmic reticulum (ER) located Ca2+ store sensor, Stromal Interaction Molecules 1-2 (STIM1/2), a pathway also termed store-operated Ca2+ entry (SOCE). The TRPM family is formed by 8 members (TRPM1-8) permeable to Mg2+, Ca2+, Zn2+ and Na+ cations, and is activated by multiple stimuli. Recent studies indicated that SOCE and TRPM structure-function are interlinked in some instances, although the molecular details of this interaction are only emerging. Here we review the role of TRPM and SOCE in Ca2+ handling and highlight the available evidence for this interaction.
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