POTASSIUM CHANNEL INACTIVATION PEPTIDE BLOCKS CYCLIC NUCLEOTIDE-GATED CHANNELS BY BINDING TO THE CONSERVED PORE DOMAIN
POTASSIUM CHANNEL INACTIVATION PEPTIDE BLOCKS CYCLIC NUCLEOTIDE-GATED CHANNELS BY BINDING TO THE CONSERVED PORE DOMAIN
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DOI：
10.1016/0896-6273(94)90220-8
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发表时间：
1994-03-01
期刊：
影响因子：
16.2
通讯作者：
SIEGELBAUM, SA
中科院分区：
文献类型：
--
作者：
KRAMER, RH;GOULDING, E;SIEGELBAUM, SA
光感受器和嗅觉神经元中的环核苷酸门控（CNG）通道由细胞内配体（cAMP和cGMP）而不是电压激活。令人惊讶的是，这些通道与电压门控通道共享氨基酸序列同源性。在这里，我们表明，CNG和电压门控通道所表现出的独特的门控机制，反映了这种结构的同源性共享功能。因此，来源于Shaker型K+通道并负责其快速失活的20个氨基酸的肽（“球肽”）也阻断CNG通道。此外，该肽选择性地阻断开放的CNG通道并防止通道关闭，表明CNC通道激活，如电压依赖性K+通道的激活，涉及位于肽结合位点的细胞内侧的门的打开。肽中的氨基酸取代引起CNG和K+通道的阻断亲和力的类似变化，表明保守的结合位点。使用嵌合的视网膜/嗅觉通道，我们表明，两个CNG通道的肽亲和力的差异是由于保守的成孔区的氨基酸序列的差异，表明该结构域形成的肽受体的一部分。
Cyclic nucleotide-gated (CNG) channels in photoreceptors and olfactory neurons are activated by intracellular ligands (cAMP and cGMP) rather than voltage. Surprisingly, these channels share amino acid sequence homology with voltage-gated channels. Here we show that the distinct gating mechanisms exhibited by CNG and voltage-gated channels share features that reflect this structural homology. Thus, a 20 amino acid peptide (''ball peptide'') derived from the Shaker-type K+ channel and responsible for its rapid inactivation also blocks CNG channels. Moreover, the peptide selectively blocks open CNG channels and prevents channel closure, showing that CNC channel activation, like activation of voltage-dependent K+ channels, involves the opening of a gate located on the intracellular side of the peptide-binding site. Amino acid substitutions in the peptide cause similar changes in blocking affinity of CNG and K+ channels, suggesting a conserved binding site. Using a chimeric retinal/olfactory channel, we show that the difference in the peptide affinity of the two CNG channels is due to a difference in the amino acid sequence of the conserved pore-forming region, demonstrating that this domain forms part of the peptide receptor.