PIP2 and PIP3 interact with N-terminus region of TRPM4 channel

Kristyna Bousova 1, Michaela Jirku 1, Ladislav Bumba 2, Jiri Vondrasek 3,
Lucie Bednarova 3, Jan Teisinger 1

1Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic
2Institute of Microbiology Academy of Sciences of the Czech Republic, Prague, Czech Republic
3 Institute of Organic chemistry and Biochemistry Academy of Sciences of the Czech Republic, Prague, Czech Republic

 

The transient receptor potential melastatin 4 (TRPM4) is a calcium-activated non-selective ion channel that plays a plethora of roles in cell sensors systems. Regulation of heart functions and control of various types of neuronal activities are among its functions relevant to human physiology and diseases. It is known that phospholipids, especially PIP2, play a unique role in the regulation of TRP channels however the molecular mechanism of this process is still unknown. We characterized the binding site of PIP2 and its homolog PIP3 in the E733-W772 region of the TRPM4 N-terminus via biophysical and molecular modeling methods. The specific positions R755 and R767 in this domain were identified as being important for interactions with PIP2/PIP3. Site-directed mutagenesis of arginine residues caused a partial loss of PIP2/PIP3 binding specifity. The binding of PIP3 to TRPM channels has never been described before. These findings provide new insight into the ligand binding domains of the TRPM4 channel.

This project was supported by Grants GACR 301/10/1159, GACR 207/11/0717 and GAUK 842313.