Independent inhibition of calcineurin and K+ currents by the immunosuppressant FK-506 in rat ventricle.
Independent inhibition of calcineurin and K+ currents by the immunosuppressant FK-506 in rat ventricle.
复制标题
免疫抑制剂 FK-506 对大鼠心室中钙调磷酸酶和 K 电流的独立抑制。
DOI：
10.1152/ajpheart.1998.275.6.h2041
复制
发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Rogers,TB
中科院分区：
文献类型：
--
作者：
duBell,WH;Gaa,ST;Lederer,WJ;Rogers,TB
FK-506通过抑制K+电流Ito和IK延长动作电位来增加大鼠心室肌细胞中的胞质Ca 2+浓度瞬变[J. Physiol.（Lond.）501：509-516，1997]。生理和生化技术被并行使用，以检查电生理机制和钙调磷酸酶抑制在这些影响中的作用。FK-506能延长Ito失活的恢复时间。因此，Ito抑制是频率依赖性的，在0.2 Hz时没有降低（在+50 mV从-70 mV记录），但在2.0 Hz时降低40%。而对IK的抑制（约60%）则不依赖于时间和电压。在25 μM时，FK-506（65%）和环孢菌素A（57%）抑制肌细胞提取物中的钙调神经磷酸酶活性。然而，只有FK-506在场刺激的心肌细胞胞浆Ca 2+浓度瞬变增加。此外，当用10 mM EGTA透析细胞时，FK-506对K+电流仍有活性。这些结果表明，钙调磷酸酶抑制不是FK-506在心脏中的功能效应的原因，并表明IKK和It 0是由FK-506结合蛋白或直接由FK-506调节的。
FK-506 increases the cytosolic Ca2+concentration transient in rat ventricular myocytes by prolonging the action potential through inhibition of the K+currentsItoandIK[J. Physiol. (Lond.)501: 509–516, 1997]. Physiological and biochemical techniques were used in parallel to examine the electrophysiological mechanisms and the role of calcineurin inhibition in these effects. FK-506 prolonged the recovery ofItofrom inactivation. ThusItoinhibition was frequency dependent, with no decrease at 0.2 Hz (recorded at +50 mV from −70 mV) but a 40% decrease at 2.0 Hz. In contrast, inhibition ofIK(∼60%) was time and voltage independent. At 25 μM, FK-506 (by 65%) and cyclosporin A (by 57%) inhibited calcineurin activity in myocyte extracts. However, only FK-506 increased the cytosolic Ca2+concentration transient in field-stimulated myocytes. Furthermore, FK-506 was still active on K+currents when cells were dialyzed with 10 mM EGTA. These results demonstrate that calcineurin inhibition is not responsible for the functional effects of FK-506 in heart and suggest thatIKandItoare modulated by FK-506-binding proteins or directly by FK-506.