Mechanism of the modulation of BK potassium channel complexes with different auxiliary subunit compositions by the omega-3 fatty acid DHA
Mechanism of the modulation of BK potassium channel complexes with different auxiliary subunit compositions by the omega-3 fatty acid DHA
复制标题
omega-3脂肪酸DHA调节具有不同辅助亚基组成的BK钾通道复合物的机制
DOI：
10.1073/pnas.1222003110
复制
发表时间：
2013-03-19
影响因子：
11.1
通讯作者：
Hou, Shangwei
中科院分区：
文献类型：
--
作者：
Hoshi, Toshinori;Tian, Yutao;Hou, Shangwei
大电导Ca 2+和电压激活的K+（BK）通道以其功能多样性而闻名，这部分是由其丰富的调节库所赋予的。我们最近发现，长链omega-3多不饱和脂肪酸，如在油性鱼类中发现的二十二碳六烯酸（DHA），通过激活由Slo 1 +β1亚基组成的血管BK通道来降低血压。在这里，我们研究了DHA对BK通道与不同的辅助亚基组成的行动。神经元Slo 1 +β4通道与血管Slo 1 +β1通道一样被DHA激活。相比之下，DHA对Slo 1 +β2、Slo 1 + LRRC 26（γ1）和无辅助亚基的Slo 1通道的刺激作用要小得多。β1、β2和β4的突变表明，DHA在Slo 1 +β1和Slo 1 +β4中的巨大作用是由于存在两个残基，一个在β1和β4亚基的N末端，另一个在第一个跨膜区段。将该氨基酸对从β1或β4转移至β2会在Slo 1 +β2中引入对DHA的较大响应。在β亚基中上述位置存在一对带相反电荷的残基与对DHA的大响应相关。Slo 1辅助亚基以高度组织依赖的方式表达。因此，DHA的亚基组成依赖性刺激表明BK通道是具有显著组织特异性的ω-3脂肪酸的效应子。
Large-conductance Ca2+- and voltage-activated K+ (BK) channels are well known for their functional versatility, which is bestowed in part by their rich modulatory repertoire. We recently showed that long-chain omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) found in oily fish lower blood pressure by activating vascular BK channels made of Slo1+β1 subunits. Here we examined the action of DHA on BK channels with different auxiliary subunit compositions. Neuronal Slo1+β4 channels were just as well activated by DHA as vascular Slo1+β1 channels. In contrast, the stimulatory effect of DHA was much smaller in Slo1+β2, Slo1+LRRC26 (γ1), and Slo1 channels without auxiliary subunits. Mutagenesis of β1, β2, and β4 showed that the large effect of DHA in Slo1+β1 and Slo1+β4 is conferred by the presence of two residues, one in the N terminus and the other in the first transmembrane segment of the β1 and β4 subunits. Transfer of this amino acid pair from β1 or β4 to β2 introduces a large response to DHA in Slo1+β2. The presence of a pair of oppositely charged residues at the aforementioned positions in β subunits is associated with a large response to DHA. The Slo1 auxiliary subunits are expressed in a highly tissue-dependent fashion. Thus, the subunit composition-dependent stimulation by DHA demonstrates that BK channels are effectors of omega-3 fatty acids with marked tissue specificity.