ATP is inarguably one of the most abundant molecules in living cells and is a fundamental energy source. The works of Holton and (1959) and Burnstock (1972) unmasked the signaling role of ATP and its metabolites in physiological systems. The purinergic receptor family is currently classified into two main groups, P1 and P2, which are receptors to adenosine and purines.
The P2X1-7 receptors form a family of seven subtypes of extracellular ATP activated cation channels. They are widely expressed in mammals and play essential roles from fast synaptic transduction to immune responses.
P2X receptor has a unique structure different from other ligand gated ion channels. It is a trimer with each subunit having two transmembrane (TM1 and TM2) domains and a huge extracellular domain harboring three intersubunit ATP binding pockets. P2X receptor requires binding of extracellular ATP to open its pore. Pore is located in center of three TM2, through which cations can pass.
We previously showed that P2X2 receptor intrinsically shows voltage dependent gating property in spite of the absence of a voltage sensor domain. Although the crystal structures in both open and closed states have been solved, it remains unknown how ATP binding changes the molecular conformation and leads the pore to change its status from closed to open. Furthermore, the voltage dependent conformational changes have not been clarified yet.
The seminar will include our recent findings on how ATP binding signal flow downstream from its binding site to open the pore and how individual subunits in the P2X2 trimer contribute upon voltage- and ATP- dependent activation. Last part of the talk will be about our recent data for the state dependent (hyperpolarized and depolarized) conformational changes in the linker region between ATP binding and transmembrane domains.
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