STUDY ON THE STRUCTURE FUNCTION AND PHYSIOLOGICAL ROLES OF SA CHANNELS

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The aim of this study was three fold : 1) elucidation of structure function of SA channels with known structure, 2) molecular identification of SA channels from higher order organisms, and 3) elucidation of roles of SA channels and cytoskeletons in mechano-induced cell signaling. Major results are as follows. (1) Identification of mechano-sensitive domain of the bacterial SA channel MscL : We found that hydrophobic amino-residues located at the peri-plasmic boundary of the lipid bilayer act as a mechanosensor of MscL. This site corresponds to the lipid glycerol backbone that is the most suitable structure for sensing tension in the membrane. (2)Molecular identification of the heart SA channel SAKCA : We cloned a gene encoding a stretch activated big Kca channel from chick heart and identified the 59 amino acids sequence called STREX at C-terminus as a mechanosensitive domain of this channel. We also isolated a 50 KDa protein acting as an accessory device that conveys tension in the membrane to STREX. (3) Role of cytosekelton in SA channel activation : We found that the stress fiber acts as a force transmitter in SA channel activation. (4) Role of SA channel in cell signaling : We analyzed the intracellular signaling leading to NF-kB activation in response to mechanical stimuli. It is suggested that cells can chose different mechano-signaling cascade depending on the time structure of mechanical stmuli. Mechano-signaling to cyclic or transient mechanical stimuli is mainly mediated by SA channels, while those to constant mechanical stimuli by integrin