ML-SI3

Last updated
ML-SI3
ML-SI3 structure.png
Identifiers
  • N-[(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl]benzenesulfonamide
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
Formula C23H31N3O3S
Molar mass 429.58 g·mol−1
3D model (JSmol)
  • COC1=CC=CC=C1N2CCN(CC2)[C@H]3CCCC[C@@H]3NS(=O)(=O)C4=CC=CC=C4
  • InChI=1S/C23H31N3O3S/c1-29-23-14-8-7-13-22(23)26-17-15-25(16-18-26)21-12-6-5-11-20(21)24-30(27,28)19-9-3-2-4-10-19/h2-4,7-10,13-14,20-21,24H,5-6,11-12,15-18H2,1H3/t20-,21-/m0/s1
  • Key:OVTXOMMQHRIKGL-SFTDATJTSA-N

ML-SI3 is a chemical compound which acts as an "antagonist" (i.e. channel blocker) of the TRPML family of calcium channels, with greatest activity at the TRPML1 channel, although it also blocks the related TRPML2 and TRPML3 channels with lower affinity. It is used for research into the role of TRPML1 and its various functions in lysosomes and elsewhere in the body. [1] [2] [3] [4] [5] [6] [7]

See also

Related Research Articles

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<span class="mw-page-title-main">Lysosome</span> Cell membrane organelle

A lysosome is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that digest many kinds of biomolecules. A lysosome has a specific composition, of both its membrane proteins and its lumenal proteins. The lumen's pH (~4.5–5.0) is optimal for the enzymes involved in hydrolysis, analogous to the activity of the stomach. Besides degradation of polymers, the lysosome is involved in cell processes of secretion, plasma membrane repair, apoptosis, cell signaling, and energy metabolism.

<span class="mw-page-title-main">Calmodulin</span> Messenger protein

Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the binding of Ca2+ is required for the activation of calmodulin. Once bound to Ca2+, calmodulin acts as part of a calcium signal transduction pathway by modifying its interactions with various target proteins such as kinases or phosphatases.

Transient receptor potential channels are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC, TRPV, TRPVL, TRPM, TRPS, TRPN TRPA. Group 2 consists of TRPP and TRPML. Other less-well categorized TRP channels exist, including yeast channels and a number of Group 1 and Group 2 channels present in non-animals. Many of these channels mediate a variety of sensations such as pain, temperature, different kinds of tastes, pressure, and vision. In the body, some TRP channels are thought to behave like microscopic thermometers and used in animals to sense hot or cold. Some TRP channels are activated by molecules found in spices like garlic (allicin), chili pepper (capsaicin), wasabi ; others are activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by molecules found in cannabis or stevia. Some act as sensors of osmotic pressure, volume, stretch, and vibration. Most of the channels are activated or inhibited by signaling lipids and contribute to a family of lipid-gated ion channels.

<span class="mw-page-title-main">TRPV6</span> Protein-coding gene in the species Homo sapiens

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Two-pore channels (TPCs) are eukaryotic intracellular voltage-gated and ligand gated cation selective ion channels. There are two known paralogs in the human genome, TPC1s and TPC2s. In humans, TPC1s are sodium selective and TPC2s conduct sodium ions, calcium ions and possibly hydrogen ions. Plant TPC1s are non-selective channels. Expression of TPCs are found in both plant vacuoles and animal acidic organelles. These organelles consist of endosomes and lysosomes. TPCs are formed from two transmembrane non-equivalent tandem Shaker-like, pore-forming subunits, dimerized to form quasi-tetramers. Quasi-tetramers appear very similar to tetramers, but are not quite the same. Some key roles of TPCs include calcium dependent responses in muscle contraction(s), hormone secretion, fertilization, and differentiation. Disorders linked to TPCs include membrane trafficking, Parkinson's disease, Ebola, and fatty liver.

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<span class="mw-page-title-main">TRPV</span> Subgroup of TRP cation channels named after the vanilloid receptor

TRPV is a family of transient receptor potential cation channels in animals. All TRPVs are highly calcium selective.

<span class="mw-page-title-main">MCOLN1</span> Protein-coding gene in the species Homo sapiens

Mucolipin-1 also known as TRPML1 is a protein that in humans is encoded by the MCOLN1 gene. It is a member of the small family of the TRPML channels, a subgroup of the large protein family of TRP ion channels.

<span class="mw-page-title-main">TRPM5</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily M member 5 (TRPM5), also known as long transient receptor potential channel 5 is a protein that in humans is encoded by the TRPM5 gene.

<span class="mw-page-title-main">TRPM8</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the TRPM8 gene. The TRPM8 channel is the primary molecular transducer of cold somatosensation in humans. In addition, mints can desensitize a region through the activation of TRPM8 receptors.

<span class="mw-page-title-main">CACNB3</span> Protein-coding gene in humans

Voltage-dependent L-type calcium channel subunit beta-3 is a protein that in humans is encoded by the CACNB3 gene.

<span class="mw-page-title-main">KCNN2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">MCOLN3</span> Protein-coding gene in the species Homo sapiens

Mucolipin-3 also known as TRPML3 is a protein that in humans is encoded by the MCOLN3 gene. It is a member of the small family of the TRPML channels, a subgroup of the large protein family of TRP ion channels.

<span class="mw-page-title-main">GCaMP</span> Genetically encoded calcium indicator

GCaMP is a genetically encoded calcium indicator (GECI) initially developed in 2001 by Junichi Nakai. It is a synthetic fusion of green fluorescent protein (GFP), calmodulin (CaM), and M13, a peptide sequence from myosin light-chain kinase. When bound to Ca2+, GCaMP fluoresces green with a peak excitation wavelength of 480 nm and a peak emission wavelength of 510 nm. It is used in biological research to measure intracellular Ca2+ levels both in vitro and in vivo using virally transfected or transgenic cell and animal lines. The genetic sequence encoding GCaMP can be inserted under the control of promoters exclusive to certain cell types, allowing for cell-type specific expression of GCaMP. Since Ca2+ is a second messenger that contributes to many cellular mechanisms and signaling pathways, GCaMP allows researchers to quantify the activity of Ca2+-based mechanisms and study the role of Ca2+ ions in biological processes of interest.

A calcium channel opener is a type of drug which facilitates ion transmission through calcium channels.

The transient receptor potential Ca2+ channel (TRP-CC) family (TC# 1.A.4) is a member of the voltage-gated ion channel (VIC) superfamily and consists of cation channels conserved from worms to humans. The TRP-CC family also consists of seven subfamilies (TRPC, TRPV, TRPM, TRPN, TRPA, TRPP, and TRPML) based on their amino acid sequence homology:

  1. the canonical or classic TRPs,
  2. the vanilloid receptor TRPs,
  3. the melastatin or long TRPs,
  4. ankyrin (whose only member is the transmembrane protein 1 [TRPA1])
  5. TRPN after the nonmechanoreceptor potential C (nonpC), and the more distant cousins,
  6. the polycystins
  7. and mucolipins.
<span class="mw-page-title-main">ML-SA1</span> Chemical compound

ML-SA1 is a chemical compound which acts as an "agonist" of the TRPML family of calcium channels. It has mainly been studied for its role in activating TRPML1 channels, although it also shows activity at the less studied TRPML2 and TRPML3 subtypes. TRPML1 is important for the function of lysosomes, and ML-SA1 has been used to study several disorders resulting from impaired lysosome function, including mucolipidosis type IV and Niemann-Pick's disease type C, as well as other conditions such as stroke and Alzheimer's disease.

<span class="mw-page-title-main">MK6-83</span> Chemical compound

MK6-83 is a chemical compound which acts as a channel opener for the TRPML family of calcium channels, with moderate selectivity for TRPML1 over the related TRPML2 and TRPML3 subtypes.

<span class="mw-page-title-main">SN-2</span> Chemical compound

SN-2 is a chemical compound which acts as an "agonist" for the TRPML3 calcium channel, with high selectivity for TRPML3 and no significant activity at the related TRPML1 and TRPML2 channels. It has demonstrated antiviral activity in an in vitro model.

References

  1. ↑ Kilpatrick BS, Yates E, Grimm C, Schapira AH, Patel S (October 2016). "Endo-lysosomal TRP mucolipin-1 channels trigger global ER Ca2+ release and Ca2+ influx". Journal of Cell Science. 129 (20): 3859–3867. doi: 10.1242/jcs.190322 . PMC   5087663 . PMID   27577094.
  2. ↑ Li X, Rydzewski N, Hider A, Zhang X, Yang J, Wang W, et al. (April 2016). "A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation". Nature Cell Biology. 18 (4): 404–17. doi:10.1038/ncb3324. hdl: 2027.42/120892 . PMID   26950892.
  3. ↑ Sahoo N, Gu M, Zhang X, Raval N, Yang J, Bekier M, et al. (May 2017). "2+ Efflux Channel in the Tubulovesicle". Developmental Cell. 41 (3): 262–273.e6. doi: 10.1016/j.devcel.2017.04.003 . PMC   5497767 . PMID   28486130.
  4. ↑ Scotto Rosato A, Montefusco S, Soldati C, Di Paola S, Capuozzo A, Monfregola J, Polishchuk E, Amabile A, Grimm C, Lombardo A, De Matteis MA, Ballabio A, Medina DL (December 2019). "TRPML1 links lysosomal calcium to autophagosome biogenesis through the activation of the CaMKKβ/VPS34 pathway". Nature Communications. 10 (1): 5630. doi:10.1038/s41467-019-13572-w. PMC   6904751 . PMID   31822666.
  5. ↑ Zhang X, Chen W, Gao Q, Yang J, Yan X, Zhao H, et al. (May 2019). "Rapamycin directly activates lysosomal mucolipin TRP channels independent of mTOR". PLoS Biology. 17 (5): e3000252. doi: 10.1371/journal.pbio.3000252 . PMC   6528971 . PMID   31112550.
  6. ↑ Li D, Shao R, Wang N, Zhou N, Du K, Shi J, et al. (March 2020). "Sulforaphane Activates a lysosome-dependent transcriptional program to mitigate oxidative stress". Autophagy: 1–16. doi:10.1080/15548627.2020.1739442. PMC   8078734 . PMID   32138578.
  7. ↑ Leser C, Keller M, Gerndt S, Urban N, Chen CC, Schaefer M, Grimm C, Bracher F (October 2020). "Chemical and pharmacological characterization of the TRPML calcium channel blockers ML-SI1 and ML-SI3". European Journal of Medicinal Chemistry: 112966. doi:10.1016/j.ejmech.2020.112966.
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