NDLI: Activation of TRPM7 channels by small molecules under physiological conditions

Content Provider	Springer Nature Link
Author	Hofmann, T. Schäfer, S. Linseisen, M. Sytik, L. Gudermann, T. Chubav, V.
Copyright Year	2014
Abstract	Transient receptor potential cation channel, subfamily M, member 7 (TRPM7) is a cation channel covalently linked to a protein kinase domain. TRPM7 is ubiquitously expressed and regulates key cellular processes such as Mg2+ homeostasis, motility, and proliferation. TRPM7 is involved in anoxic neuronal death, cardiac fibrosis, and tumor growth. The goal of this work was to identify small molecule activators of the TRPM7 channel and investigate their mechanism of action. We used an aequorin bioluminescence-based assay to screen for activators of the TRPM7 channel. Valid candidates were further characterized using patch clamp electrophysiology. We identified 20 drug-like compounds with various structural backbones that can activate the TRPM7 channel. Among them, the δ opioid antagonist naltriben was studied in greater detail. Naltriben’s action was selective among the TRP channels tested. Naltriben activates TRPM7 currents without prior depletion of intracellular Mg2+ even under conditions of low PIP2. Moreover, naltriben interfered with the effect of the TRPM7 inhibitor NS8593. Finally, our experiments with TRPM7 variants carrying mutations in the pore, TRP, and kinase domains indicate that the site of TRPM7 activation by this small-molecule ligand is most likely located in or near the TRP domain. In conclusion, we identified the first organic small-molecule activators of TRPM7 channels, thus providing new experimental tools to study TRPM7 function in native cellular environments.
Starting Page	2177
Ending Page	2189
Page Count	13
File Format	PDF
ISSN	00316768
Journal	Pflügers Archiv
Volume Number	466
Issue Number	12
e-ISSN	14322013
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2014-03-15
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	TRPM7 Magnesium Calcium Phosphatidylinositol 4,5-bisphosphate Naltriben δ opioids Human Physiology
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Clinical Biochemistry

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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