Molecular basis for exaggerated sensitivity to mexiletine in the cardiac isoform of the fast Na channel

FEBS Letters

Seyama, Issei¹  Yamaoka, Kaoru¹  Fujimoto, Yoshinori²  Yuki, Tsunetsugu¹  Maejima, Hiroshi³  Kinoshita, Eiji¹  Kawagoe, Hiroyuki¹ 

[1] Department of Physiology, School of Medicine, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan;Department of Orthopaedic Surgery, School of Medicine, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan;Institute of Health Science, School of Medicine, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan

关键词: Mexiletine;    Na channel;    Block;    Whole-cell patch clamp;    HEK 293;    HEK;    human embryonic kidney;    rBII;    α-subunit of a rat brain type II Na+ channel;    rH1;    α-subunit of a rat cardiac-specific Na+ channel;    μ1;    α-subunit of rat skeletal muscle Na+ channel;    LA;    local anesthetic;   

DOI  :  10.1016/S0014-5793(02)02320-7

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Cardiac sodium channels have been shown to have a higher sensitivity to local anesthetic agents, such as lidocaine, than the sodium channels of other tissues. To examine if this is also true for mexiletine, we have systematically measured mexiletine sensitivity of the Na channel isoforms, rH1, μ1, and rBII, which were transiently expressed in human embryonic kidney (HEK) 293 cells. We confirmed that the cardiac isoform rH1 exhibited the highest sensitivity among the three tested channel isoforms. In rH1, μ1, and rBII, the respective IC₅₀ values were 62, 294, and 308 μM mexiletine, in regard to tonic block, and 18, 54, and 268 μM mexiletine, in relation to use (8 Hz)-dependent block. The relatively high drug sensitivity of rH1 was an invariant finding, irrespective of channel state or whether channels were subjected to infrequent or frequent depolarizing stimuli. Mutating specific amino acids in the skeletal muscle isoform μ1 (namely, μ1-I433V and μ1-S251A) to those of the cardiac isoform at putative binding sites for local anesthetic agents revealed that only one of the point mutations (μ1-S251A) has relevance to the high cardiac drug sensitivity, because mexiletine produced significantly more use-dependent and tonic block in μ1-S251A than wild-type μ1.

【 授权许可】

Unknown