Molecular basis of fast inactivation in voltage and Ca2+-activated K+ channels:: A transmembrane β-subunit homolog
Molecular basis of fast inactivation in voltage and Ca2+-activated K+ channels:: A transmembrane β-subunit homolog
复制标题
DOI：
10.1073/pnas.96.7.4137
复制
发表时间：
1999-03-30
影响因子：
11.1
通讯作者：
Toro, L
中科院分区：
文献类型：
--
作者：
Wallner, M;Meera, P;Toro, L
电压依赖性和钙敏感K+(Maxik)通道是神经元兴奋性、分泌和血管张力的关键调节器，因为它们能够感知跨膜电压和细胞内钙离子。在大多数组织中，它们的刺激导致非失活的超极化K+电流降低兴奋性，除了非失活的Maxik电流，在嗜铬细胞和海马神经元等细胞中发现失活的Maxik通道表型，失活的Maxik通道的分子决定因素尚不清楚。在这里，我们报告了一个跨膜β亚基(β2)，它与形成孔的Maxik通道的α亚基共表达时产生失活的Maxik电流。在细胞内应用胰酶以及删除β2亚基的19个N端氨基酸可以消除α亚基的失活。相反，这些N端氨基酸与非失活的平滑肌β1亚单位的融合导致了Maxik通道的失活表型。此外，加入合成的β2亚基的N端肽，通过阻断其K+传导孔而导致Maxik通道α亚基的失活，类似于电压依赖的K+通道中的“球”肽引起的失活。因此，天然组织中MAXIK通道的失活表型可能是与不同的β亚基相关联的结果。
Voltage-dependent and calcium sensitive K+ (MaxiK) channels are key regulators of neuronal excitability, secretion, and vascular tone because of their ability to sense transmembrane voltage and intracellular Ca2+. In most tissues, their stimulation results in a noninactivating hyperpolarizing K+ current that reduces excitability, In addition to noninactivating MaxiK currents, an inactivating MaxiK channel phenotype is found in cells like chromaffin cells and hippocampal neurons, The molecular determinants underlying inactivating MaxiK channels remain unknown. Herein, we report a transmembrane beta subunit (beta 2) that yields inactivating MaxiK currents on coexpression with the pore-forming alpha subunit of MaxiK channels. Intracellular application of trypsin as well as deletion of 19 N-terminal amino acids of the beta 2 subunit abolished inactivation of the alpha subunit. Conversely, fusion of these N-terminal amino acids to the noninactivating smooth muscle beta 1 subunit leads to an inactivating phenotype of MaxiK channels. Furthermore, addition of a synthetic N-terminal peptide of the beta 2 subunit causes inactivation of the MaxiK channel alpha subunit by occluding its K+-conducting pore resembling the inactivation caused by the "ball" peptide in voltage-dependent K+ channels. Thus, the inactivating phenotype of MaxiK channels in native tissues can result from the association with different beta subunits.