Cell Calcium. 2012 Feb;51(2):179-85. doi: 10.1016/j.ceca.2011.12.011. Epub 2012 Jan 4.

The juvenile myoclonic epilepsy-related protein EFHC1 interacts with the redox-sensitive TRPM2 channel linked to cell death.External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c

Katano, M., Numata, T., Aguan, K., Hara, Y., Kiyonaka, S., Yamamoto, S., Miki, T., Sawamura, S., Suzuki, T., Yamakawa, K., Mori, Y.,
["Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan."]
The transient receptor potential M2 channel (TRPM2) is the Ca(2+)-permeable cation channel controlled by cellular redox status via beta-NAD(+) and ADP-ribose (ADPR). TRPM2 activity has been reported to underlie susceptibility to cell death and biological processes such as inflammatory cell migration and insulin secretion. However, little is known about the intracellular mechanisms that regulate oxidative stress-induced cell death via TRPM2. We report here a molecular and functional interaction between the TRPM2 channel and EF-hand motif-containing protein EFHC1, whose mutation causes juvenile myoclonic epilepsy (JME) via mechanisms including neuronal apoptosis. In situ hybridization analysis demonstrates TRPM2 and EFHC1 are coexpressed in hippocampal neurons and ventricle cells, while immunoprecipitation analysis demonstrates physical interaction of the N- and C-terminal cytoplasmic regions of TRPM2 with the EFHC1 protein. Coexpression of EFHC1 significantly potentiates hydrogen peroxide (H(2)O(2))- and ADPR-induced Ca(2+) responses and cationic currents via recombinant TRPM2 in HEK293 cells. Furthermore, EFHC1 enhances TRPM2-conferred susceptibility of HEK293 cells to H(2)O(2)-induced cell death, which is reversed by JME mutations. These results reveal a positive regulatory action of EFHC1 on TRPM2 activity, suggesting that TRPM2 contributes to the expression of JME phenotypes by mediating disruptive effects of JME mutations of EFHC1 on biological processes including cell death.
PMID: 22226147External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c
Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Screening Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vitro validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vivo validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Characterization Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Functional consequence Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b top
Screening Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Experimental screening Non-experimental screening Reference
TRP channel construct Interactor source
TRP channel Interactor Method Species Region Species Organ/tissue Sample type
TRPM2 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 EFHC1 Inference Prediction 22226147
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Screening Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vitro validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vivo validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Characterization Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Functional consequence Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b top
Validation: In vivo validation Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Assay with endogenous proteins Assay with overexpressed proteins Reference
Cell or tissue Cell or tissue TRP channel construct Interactor construct
TRP channel Interactor Method Species Region Species Region
TRPM2 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 EFHC1 Co-immunoprecipitation Mouse brain microsome extracts 22226147
TRPM2 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 EFHC1 Co-immunoprecipitation HEK293 Human Full-length Mouse 319-1376 22226147
TRPM2 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 EFHC1 Co-immunofluorescence staining HEK293 Human Full-length Mouse 319-1376 22226147
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Screening Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vitro validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vivo validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Characterization Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Functional consequence Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b top
Characterization Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Binding region mapping Stoichiometry Affinity (Kd) Reference
TRP channel Interactor
TRP channel Interactor Method Species Region Species Region
TRPM2 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 EFHC1 Co-immunoprecipitation Human 1-2214 Mouse Not determined 22226147
TRPM2 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 EFHC1 Co-immunoprecipitation Human 3169-4509 Mouse Not determined 22226147
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Screening Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vitro validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vivo validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Characterization Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Functional consequence Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b top
Functional consequence Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
TRP channel Interactor Method Post-translational modification Subcellular trafficking Activity Reference
TRPM2 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 EFHC1 Patch clamp Activation 22226147
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
TRP / Interactor

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