| Research Abstract |
1.MaxiK channel is the large-conductance, voltage-dependent and Ca^<2+> K^+ channel. This channel is almost ubiquitously distributed among mammalian tissues including smooth muscles. MaxiK activation mediates relaxations to a variety of physiological substances whereas its inhibition plays a significant role in contractile responses.
2.In the present study, the roles of MaxiK channel in the regulation of smooth muscle mechanical activity and its molecular mechanisms were further investigated for our better understating of the channel, and we obtained the following new findings.
3.Arterial and tracheal smooth muscle relaxations mediated through Gs-protein-coupled receptors such as β (β1, β2 andβ3)-adrenoceptors and IP receptor were elicited through cAMP-independent pathway as well as a cAMP-dependent route. Inβ2-adrenoceptor and IP-receptor-mediated relaxations, both mechanisms included MaxiK channel activation. Electrophysiological and mechanical studies with cholera toxin and GTP analog
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ues indicated that cAMP-independent relaxant mechanism is partly attributed to a direct activation of this channel by Gs-protein. Inβ3-receptor-mediated relaxation, delayed rectified K^+ channel but not MaxiK channel accounts for cAMP-independent relaxant mechanisms.
4.In urinary bladder smooth muscle, MaxiK channel was demonstrated to function as a primary negative feedback element to limit extracellular Ca^<2+> influx through affecting action potential configurations in the generation of this muscle spontaneous myogenic contraction. MaxiK channel openers including β1-subunit activators may be a potentially useful therapeutic remedy for the treatment of urinary bladder dysfunctions such as frequent urination.
5.These results support the key role of MaxiK channel as a rheostat fine tuning membrane potential and intracellular Ca^<2+> to control smooth muscle mechanical activity and indicate the substantial contribution of Gs-protein-mediated direct channel regulation. In the next step, we are planning to reveal the physiological of MaxiK channelβ1-subunit usingβ1-subunit-deleted mice with paying attention especially to smooth muscle constrictors such as thromboxane A2. Less
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