Document Detail

Sphingosine and FTY720 are potent inhibitors of the transient receptor potential melastatin 7 (TRPM7) channels.
MedLine Citation:
PMID:  23145923     Owner:  NLM     Status:  MEDLINE    
BACKGROUND AND PURPOSE: Transient receptor potential melastatin 7 (TRPM7) is a unique channel kinase which is crucial for various physiological functions. However, the mechanism by which TRPM7 is gated and modulated is not fully understood. To better understand how modulation of TRPM7 may impact biological processes, we investigated if TRPM7 can be regulated by the phospholipids sphingosine (SPH) and sphingosine-1-phosphate (S1P), two potent bioactive sphingolipids that mediate a variety of physiological functions. Moreover, we also tested the effects of the structural analogues of SPH, N,N-dimethyl-D-erythro-sphingosine (DMS), ceramides and FTY720 on TRPM7.
EXPERIMENTAL APPROACH: HEK293 cells stably expressing TRPM7 were used for whole-cell, single-channel and macropatch current recordings. Cardiac fibroblasts were used for native TRPM7 current recording.
KEY RESULTS: SPH potently inhibited TRPM7 in a concentration-dependent manner, whereas S1P and other ceramides did not produce noticeable effects. DMS also markedly inhibited TRPM7. Moreover, FTY720, an immunosuppressant and the first oral drug for treatment of multiple sclerosis, inhibited TRPM7 with a similar potency to that of SPH. In contrast, FTY720-P has no effect on TRPM7. It appears that SPH and FTY720 inhibit TRPM7 by reducing channel open probability. Furthermore, endogenous TRPM7 in cardiac fibroblasts was markedly inhibited by SPH, DMS and FTY720.
CONCLUSIONS AND IMPLICATIONS: This is the first study demonstrating that SPH and FTY720 are potent inhibitors of TRPM7. Our results not only provide a new modulation mechanism of TRPM7, but also suggest that TRPM7 may serve as a direct target of SPH and FTY720, thereby mediating S1P-independent physiological/pathological functions of SPH and FTY720.
Xin Qin; Zhichao Yue; Baonan Sun; Wenzhong Yang; Jia Xie; Eric Ni; Yi Feng; Rafat Mahmood; Yanhui Zhang; Lixia Yue
Related Documents :
9830063 - Human phosphoinositide 3-kinase c2beta, the role of calcium and the c2 domain in enzyme...
23251633 - Hexachlorophene is a potent kcnq1/kcne1 potassium channel activator which rescues lqts ...
19225163 - Determination of apparent calcium affinity for endogenously expressed human sarco(endo)...
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  British journal of pharmacology     Volume:  168     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-25     Completed Date:  2013-08-23     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1294-312     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Cells, Cultured
HEK293 Cells
Immunosuppressive Agents / chemistry,  metabolism,  pharmacology
Membrane Potentials / drug effects*
Membrane Transport Modulators / chemistry,  metabolism,  pharmacology*
Myocytes, Cardiac / cytology,  drug effects*,  metabolism
Organophosphates / pharmacology
Propylene Glycols / pharmacology*
Protein Kinase Inhibitors / analogs & derivatives,  metabolism,  pharmacology*
Recombinant Proteins / antagonists & inhibitors,  metabolism
Sphingosine / analogs & derivatives*,  chemistry,  metabolism*,  pharmacology
TRPM Cation Channels / antagonists & inhibitors*,  genetics,  metabolism
Grant Support
Reg. No./Substance:
0/FTY 720P; 0/Immunosuppressive Agents; 0/Membrane Transport Modulators; 0/Organophosphates; 0/Propylene Glycols; 0/Protein Kinase Inhibitors; 0/Recombinant Proteins; 0/TRPM Cation Channels; 0/TRPM6 protein, human; 0/Trpm6 protein, mouse; 122314-67-4/N,N-dimethylsphingosine; 3QN8BYN5QF/fingolimod; EC 2.7.1.-/TRPM7 protein, human; EC 2.7.1.-/Trpm7 protein, mouse; NGZ37HRE42/Sphingosine
Comment In:
Br J Pharmacol. 2013 Mar;168(6):1291-3   [PMID:  23186176 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Pharmaceutical care issues identified by pharmacists in patients with diabetes, hypertension or hype...
Next Document:  Phenolics and their Antifungal Role in Grapevine Wood Decay: Focus on the Botryosphaeriaceae Family.