Molecular mechanism of calcium channel regulation in the fight-or-flight response.
Molecular mechanism of calcium channel regulation in the fight-or-flight response.
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DOI：
10.1126/scisignal.2001152
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发表时间：
2010-09-28
影响因子：
7.3
通讯作者：
Catterall WA
中科院分区：
文献类型：
--
作者：
Fuller MD;Emrick MA;Sadilek M;Scheuer T;Catterall WA
在战斗或逃跑反应中，交感神经系统通过激活β-肾上腺素能受体、腺苷酸环化酶和腺苷3 ',5 ' -单磷酸依赖蛋白激酶（也称为蛋白激酶A (PKA)）的磷酸化，刺激由CaV1通道传导的l型钙离子（Ca2+）电流，增加骨骼肌和心肌的收缩性。我们通过形成一个由CaV1.2Δ1800（一种在体内蛋白水解加工位点截断的通道形式）、其非共价相关的远端羧基末端结构域、辅助α2δ1和β2b亚基以及a激酶锚定蛋白15 （AKAP15）组成的自抑制信号复合物，重构了非肌肉细胞中心脏CaV1.2通道的调节。观察到CaV1.2通道活性的3.6倍范围，从蛋白激酶抑制剂存在时的最小值到腺苷酸环化酶激活时的最大值。在未受刺激的细胞中，基础的CaV1.2通道活性是由位于远端和近端羧基末端调节域之间的两个残基丝氨酸-1700和苏氨酸-1704的磷酸化调控的，而通过PKA信号通路进一步刺激通道活性只需要磷酸化丝氨酸-1700。我们的研究结果定义了CaV1.2通道调控的概念框架，并确定了调节通道活性的磷酸化位点。
During the fight-or-flight response, the sympathetic nervous system stimulates L-type calcium ion (Ca2+) currents conducted by CaV1 channels through activation of β-adrenergic receptors, adenylyl cyclase, and phosphorylation by adenosine 3′,5′-monophosphate–dependent protein kinase [also known as protein kinase A (PKA)], increasing contractility of skeletal and cardiac muscles. We reconstituted this regulation of cardiac CaV1.2 channels in non-muscle cells by forming an autoinhibitory signaling complex composed of CaV1.2Δ1800 (a form of the channel truncated at the in vivo site of proteolytic processing), its noncovalently associated distal carboxyl-terminal domain, the auxiliary α2δ1 and β2b subunits, and A-kinase anchoring protein 15 (AKAP15). A factor of 3.6 range of CaV1.2 channel activity was observed from a minimum in the presence of protein kinase inhibitors to a maximum upon activation of adenylyl cyclase. Basal CaV1.2 channel activity in unstimulated cells was regulated by phosphorylation of serine-1700 and threonine-1704, two residues located at the interface between the distal and the proximal carboxyl-terminal regulatory domains, whereas further stimulation of channel activity through the PKA signaling pathway only required phosphorylation of serine-1700. Our results define a conceptual framework for CaV1.2 channel regulation and identify sites of phosphorylation that regulate channel activity.
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DOI：
10.1073/pnas.88.23.10778
发表时间：
1991-12-01
影响因子：
11.1
作者：
DEJONGH, KS;WARNER, C;CATTERALL, WA
通讯作者：
CATTERALL, WA
DOI：
10.1073/pnas.93.8.3362
发表时间：
1996-04-16
影响因子：
11.1
作者：
Hell, JW;Westenbroek, RE;Catterall, WA
通讯作者：
Catterall, WA
影响因子：
16.2
作者：
Gray, PC;Johnson, BD;Murphy, BJ
通讯作者：
Murphy, BJ
影响因子：
11.4
作者：
Fraser, IDC;Tavalin, SJ;Scott, JD
通讯作者：
Scott, JD
影响因子：
7.3
作者：
DAVIS, PD;ELLIOTT, LH;WILKINSON, SE
通讯作者：
WILKINSON, SE