Mechanism of tetrodotoxin block and resistance in sodium channels

详细信息    查看全文

• 作者：Rong Chen ; ^{rong.chen@anu.edu.au" class="auth_mail} ; Shin-Ho Chung
• 关键词：MD ; molecular dynamics ; NaV ; voltage-gated sodium ; PMF ; potential of mean force ; TTX ; tetrodotoxin
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：28 March, 2014
• 年：2014
• 卷：446
• 期：1
• 页码：370-374
• 全文大小：849 K

文摘

Tetrodotoxin (TTX) has been used for many decades to characterize the structure and function of biological ion channels. Yet, the precise mechanism by which TTX blocks voltage-gated sodium (Na_V) channels is not fully understood. Here molecular dynamics simulations are used to elucidate how TTX blocks mammalian voltage-gated sodium (Nav) channels and why it fails to be effective for the bacterial sodium channel, Na_VAb. We find that, in Na_VAb, a sodium ion competes with TTX for the binding site at the extracellular end of the filter, thus reducing the blocking efficacy of TTX. Using a model of the skeletal muscle channel, Na_V1.4, we show that the conduction properties of the channel observed experimentally are faithfully reproduced. We find that TTX occludes the entrance of Na_V1.4 by forming a network of hydrogen-bonds at the outer lumen of the selectivity filter. The guanidine group of TTX adopts a lateral orientation, rather than pointing into the filter as proposed previously. The acidic residues just above the selectivity filter are important in stabilizing the hydrogen-bond network between TTX and Na_V1.4. The effect of two single mutations of a critical tyrosine residue in the filter of Na_V1.4 on TTX binding observed experimentally is reproduced using computational mutagenesis.