McDonough S I, Bean B P
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Mol Pharmacol. 1998 Dec;54(6):1080-7. doi: 10.1124/mol.54.6.1080.
The antihypertensive agent mibefradil completely and reversibly inhibited T-type calcium channels in freshly isolated rat cerebellar Purkinje neurons. The potency of mibefradil was increased at less hyperpolarized holding potentials, and the apparent affinity was correlated with the degree of channel inactivation. At 35 degrees, the apparent dissociation constant Kapp was 1 microM at a holding voltage of -110 mV (corresponding to noninactivated channels) and 83 nM at a holding voltage of -70 mV (corresponding to 65% inactivation). The increased affinity was attributable mainly to a decreased off-rate. Mibefradil also inhibited P-type calcium channels in Purkinje neurons, but inhibition was much less potent. At a holding potential of -70 mV, the Kapp for mibefradil inhibition of P-type channels was approximately 200-fold higher than that for inhibition of T-type channels. Mibefradil should be a useful compound for distinguishing T-type channels from high voltage-activated calcium channels in neurons studied in vitro.
抗高血压药米贝地尔能完全且可逆地抑制新鲜分离的大鼠小脑浦肯野神经元中的T型钙通道。在去极化程度较低的钳制电位下，米贝地尔的效力增强，其表观亲和力与通道失活程度相关。在35摄氏度时，钳制电压为-110 mV（对应非失活通道）时，米贝地尔的表观解离常数Kapp为1微摩尔，钳制电压为-70 mV（对应65%失活）时为83纳摩尔。亲和力增加主要归因于解离速率降低。米贝地尔也抑制浦肯野神经元中的P型钙通道，但抑制作用弱得多。在钳制电位为-70 mV时，米贝地尔抑制P型通道的Kapp比抑制T型通道的Kapp高约200倍。在体外研究的神经元中，米贝地尔应该是一种区分T型通道与高电压激活钙通道的有用化合物。
