* Identification and Characterization of a Novel Large-Conductance Calcium-Activated Potassium Channel Activator, CTIBD, and Its Relaxation Effect on Urinary Bladder Smooth Muscle.
- The large-conductance calcium-activated potassium channel (BKCa channel) is expressed on various tissues and is involved in smooth muscle relaxation. The channel is highly expressed on urinary bladder smooth muscle cells and regulates the repolarization phase of the spontaneous action potentials that control muscle contraction. To discover novel chemical activators of the BKCa channel, we screened a chemical library containing 8364 chemical compounds using a cell-based fluorescence assay. A chemical compound containing an isoxazolyl benzene skeleton (compound 1) was identified as a potent activator of the BKCa channel and was structurally optimized through a structure-activity relationship study to obtain 4-(4-(4-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol (CTIBD). When CTIBD was applied to the treated extracellular side of the channel, the conductance-voltage relationship of the channel shifted toward a negative value, and the maximum conductance increased in a concentration-dependent manner. CTIBD altered the gating kinetics of the channel by dramatically slowing channel closing without effecting channel opening. The effects of CTIBD on bladder muscle relaxation and micturition function were tested in rat tissue and in vivo. CTIBD concentration-dependently reduced acetylcholine-induced contraction of urinary bladder smooth muscle strips. In an acetic acid-induced overactive bladder (OAB) model, intraperitoneal injection of 20 mg/kg CTIBD effectively restored frequent voiding contraction and lowered voiding volume without affecting other bladder function parameters. Thus, our results indicate that CTIBD and its derivatives are novel chemical activators of the bladder BKCa channel and potential candidates for OAB therapeutics. SIGNIFICANCE STATEMENT: The novel BKCa channel activator CTIBD was identified and characterized in this study. CTIBD directly activates the BKCa channel and relaxes urinary bladder smooth muscle of rat, so CTIBD can be a potential candidate for overactive bladder therapeutics.
=>1.機能, 関数, 役割, 働き, 2.機能する, 作用する, 働く, 役目を果たす, 3.社交的会合, パーティー, 儀式
Overview of noun function
The noun function has 7 senses (first 3 from tagged texts)
1. (43) function, mathematical function, single-valued function, map, mapping -- ((mathematics) a
mathematical relation such that each element of a given set (the domain of the function) is
associated with an element of another set (the range of the function))
2. (24) function, purpose, role, use -- (what something is used for; "the function of an auger is to
bore holes"; "ballet is beautiful but what use is it?")
3. (7) function, office, part, role -- (the actions and activities assigned to or required or
expected of a person or group; "the function of a teacher"; "the government must do its part"; "play
its role")
4. function -- (a relation such that one thing is dependent on another; "height is a function of
age"; "price is a function of supply and demand")
5. function -- (a formal or official social gathering or ceremony; "it was a black-tie function")
6. affair, occasion, social occasion, function, social function -- (a vaguely specified social
event; "the party was quite an affair"; "an occasion arranged to honor the president"; "a seemingly
endless round of social functions")
7. routine, subroutine, subprogram, procedure, function -- (a set sequence of steps, part of larger
computer program)
Overview of verb function
The verb function has 3 senses (first 3 from tagged texts)
1. (9) function, work, operate, go, run -- (perform as expected when applied; "The washing machine
won't go unless it's plugged in"; "Does this old car still run well?"; "This old radio doesn't work
anymore")
2. (3) serve, function -- (serve a purpose, role, or function; "The tree stump serves as a table";
"The female students served as a control group"; "This table would serve very well"; "His freedom
served him well"; "The table functions as a desk")
3. (1) officiate, function -- (perform duties attached to a particular office or place or function;
"His wife officiated as his private secretary")
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