Allosteric modulation of Ca2+ channels by G proteins, voltage-dependent facilitation, protein kinase C, and Cavβ subunits
Allosteric modulation of Ca2+ channels by G proteins, voltage-dependent facilitation, protein kinase C, and Cavβ subunits
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DOI：
10.1073/pnas.051628998
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发表时间：
2001-04-10
影响因子：
11.1
通讯作者：
Catterall, WA
中科院分区：
文献类型：
--
作者：
Herlitze, S;Zhong, HJ;Catterall, WA
N型和P/Q型钙通道被神经递质抑制，神经递质通过C蛋白偶联受体作用于涉及Gβγ亚基的膜限定通路。抑制是由于从容易激活的“愿意”(W)状态转变到更难激活的“不情愿”(R)状态引起的。这种抑制可以被强烈的去极化逆转，导致脉冲前促进，或通过蛋白激酶C(PKC)的磷酸化。含Cav2.2aα(1)亚基的N型钙通道和含Ca(V)2.1α(1)亚基的P/Q型钙通道的调节差异显著。在没有G蛋白调节的情况下，含有Ca(V)β亚基的Ca(V)2.1通道处于紧张态，而不含β亚基的Ca(V)2.1通道和含有β亚基的Ca(V)2.2a通道处于紧张态。Ca(V)2.1和Ca(V)2.2a通道均可通过强去极化或PKC磷酸化而返回W态。我们的结果表明，在没有C蛋白调节的情况下，R状态及其通过脉冲前促进、PKC磷酸化和Ca(V)β亚基的调节是钙通道本身的固有特性。一个常见的G蛋白调节钙通道活性的变构模型包含了α(1)亚基的W态和R态之间的内在平衡，以及C蛋白、Ca(V)β亚基、膜去极化和PKC的磷酸化对这种平衡的调节。这种调节将调节突触的传递，这些突触使用N型和P/Q型钙通道来启动神经递质的释放。
N-type and P/Q-type Ca2+ channels are inhibited by neurotransmitters acting through C protein-coupled receptors in a membrane-delimited pathway involving G beta gamma subunits. Inhibition is caused by a shift from an easily activated "willing" (W) state to a more-difficult-to-activate "reluctant" (R) state. This inhibition can be reversed by strong depolarization, resulting in prepulse facilitation, or by protein kinase C (PKC) phosphorylation. Comparison of regulation of N-type Ca2+ channels containing Cav2.2a alpha (1) subunits and P/Q-type Ca2+ channels containing Ca(v)2.1 alpha (1) subunits revealed substantial differences. In the absence of G protein modulation, Ca(v)2.1 channels containing Ca(v)beta subunits were tonically in the W state, whereas Ca(v)2.1 channels without beta subunits and Ca(v)2.2a channels with beta subunits were tonically in the R state. Both Ca(v)2.1 and Ca(v)2.2a channels could be shifted back toward the W state by strong depolarization or PKC phosphorylation. Our results show that the R state and its modulation by prepulse facilitation, PKC phosphorylation, and Ca(v)beta subunits are intrinsic properties of the Ca2+ channel itself in the absence of C protein modulation. A common allosteric model of G protein modulation of Ca2+-channel activity incorporating an intrinsic equilibrium between the Wand R states of the alpha (1) subunits and modulation of that equilibrium by C proteins, Ca(v)beta subunits, membrane depolarization, and phosphorylation by PKC accommodates our findings. Such regulation will modulate transmission at synapses that use N-type and P/Q-type Ca2+ channels to initiate neurotransmitter release.