Summary of efforts to identify compounds that inhibit transient receptor potential cation channel C4 (TRPC4)
Assay Implementation: Meng Wu Ph.D., Melissa Miller, Amy Scott M.S., Shunyou Long M.S., Kaiping Xu M.S., Bill Shi Ph.D., David Meyers Ph.D., Jia Xu Ph.D. ..more
Source (MLPCN Center Name): Johns Hopkins Ion Channel Center (JHICC)
Center Affiliation: Johns Hopkins University, School of Medicine
Screening Center PI: Min Li, Ph.D.
Assay Provider: Michael Zhu, Ph.D., Ohio State University
Network: Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1 R21 NS056942-01
Grant Proposal PI: Michael Zhu, Ph.D., Ohio State University
Assay Implementation: Meng Wu Ph.D., Melissa Miller, Amy Scott M.S., Shunyou Long M.S., Kaiping Xu M.S., Bill Shi Ph.D., David Meyers Ph.D., Jia Xu Ph.D.
Name: Primary cell-based screen for identification of compounds that inhibit transient receptor potential cation channel C4 (TRPC4).
Transient receptor potential (TRP) channels act as key regulators of many sensory systems including those for thermo-, photo-, and osmosensation [1-3]. A diversity of biological disorders has been linked to TRP channel malfunction ranging from neuropathic pain , cardiovascular diseases , to other diseases involving sensory physiology [6,7].
The TRP family of cation channels can be separated into seven subtypes according to structural similarity. Members of this family are nonselective cation channels that allow entry of extracellular calcium into cells resulting in a depolarization of membrane potential . The mammalian TRPC (canonical) subfamily is proposed to function as store and second-messenger operated cation channels . Disruption of TRPC may cause aberrant modulation of intracellular calcium and changes in membrane potential leading to activation of transcription factors, apoptosis, vascular contractility, platelet activation, and cardiac hypertrophy. Currently there are few pharmacological modulators of the TRPC family and no compounds known to target specific TRPC isoforms .
This assay summarizes the efforts in identification of test compounds
that inhibit transient receptor potential cation channel C4 (TRPC4). It is still ongoing at JHICC.
1. Venkatachalam, K., and Montell, C. TRP Channels. Annual Review of Biochemistry 76(1), 387-417 (2007) PMID: 17579562
2. Clapham, D., Julius, D., Montell, C. and Schultz, G. International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels. Pharmacological Reviews 57(4), 427-450 (2005) PMID: 16382100
3. Reaves, B. J., and Wolstenholme, A. J. The TRP channel superfamily: insights into how structure, protein-lipid interactions and localization influence function. Biochemical Society Transactions 035(1), 77-80 (2007) PMID: 17233605
4. Patapoutian, A., Tate, S., and Woolf, C. J. Transient receptor potential channels: targeting pain at the source. Nat Rev Drug Discov 8(1), 55-68 (2009) PMID: 19116627
5. Vassort G, Alvarez J. Transient receptor potential: a large family of new channels of which several are involved in cardiac arrhythmia. Can J Physiol Pharmacol. 2009 Feb;87(2):100-7.PMID: 19234573
6. Nilius, B. TRP channels in disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1772(8), 805-812 (2007) PMID: 17368864
7. Woudenberg-Vrenken, T. E., Bindels, R. J. M., and Hoenderop, J. G. J. The role of transient receptor potential channels in kidney disease. Nat Rev Nephrol 5(8), 441-449 (2009) PMID: 19546862
8. Zhu, X., Jiang, M., Peyton, M., et al. trp, a Novel Mammalian Gene Family Essential for Agonist-Activated Capacitative Ca2+ Entry. Cell 85(5), 661-671 (1996) PMID: 8646775
9. Abramowitz, J., and Birnbaumer, L. Physiology and pathophysiology of canonical transient receptor potential channels. FASEB J. 23(2), 297-328 (2009) PMID: 18940894
10. Okuhara, D. Y., Hsia, A. Y., and Xie, M. Transient receptor potential channels as drug targets. Expert Opinion on Therapeutic Targets 11(3), 391-401 (2007) PMID: 17298296
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML204
PubChem Substance ID (SID) for probe 1: 97362164
PubChem Compound ID (CID) for probe 1: 230710
Probe type for probe 1: Inhibitor
IC50/EC50 (nM) for probe 1: 960 +/- 260
Target for probe 1: TRPC4 inhibitor _?OR activation (gi: 2935630)
Anti-target for probe 1: TRPC6 inhibitor_Ach activation
Fold selectivity for probe 1: 19
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK65430/ (ID: 2642530)
Grant number for probe 1: NS056942-01
PubMed Publication ID (PMID) for probe 1: 21795696
NCBI Book chapter title for probe 1: Novel Chemical Inhibitor of TRPC4 Channels
Data Table (Concise)