Walker Simon A, Kupzig Sabine, Bouyoucef Dalila, Davies Louise C, Tsuboi Takashi, Bivona Trever G, Cozier Gyles E, Lockyer Peter J, Buckler Alan, Rutter Guy A, Allen Maxine J, Philips Mark R, Cullen Peter J
Inositide Group, Henry Wellcome Integrated Signalling Laboratories, Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, UK.
EMBO J. 2004 Apr 21;23(8):1749-60. doi: 10.1038/sj.emboj.7600197. Epub 2004 Apr 1.
Receptor-mediated increases in the concentration of intracellular free calcium ([Ca2+]i) are responsible for controlling a plethora of physiological processes including gene expression, secretion, contraction, proliferation, neural signalling, and learning. Increases in [Ca2+]i often occur as repetitive Ca2+ spikes or oscillations. Induced by electrical or receptor stimuli, these repetitive Ca2+ spikes increase their frequency with the amplitude of the receptor stimuli, a phenomenon that appears critical for the induction of selective cellular functions. Here we report the characterisation of RASAL, a Ras GTPase-activating protein that senses the frequency of repetitive Ca2+ spikes by undergoing synchronous oscillatory associations with the plasma membrane. Importantly, we show that only during periods of plasma membrane association does RASAL inactivate Ras signalling. Thus, RASAL senses the frequency of complex Ca2+ signals, decoding them through a regulation of the activation state of Ras. Our data provide a hitherto unrecognised link between complex Ca2+ signals and the regulation of Ras.
受体介导的细胞内游离钙浓度（[Ca2+]i）升高负责控制大量生理过程，包括基因表达、分泌、收缩、增殖、神经信号传导和学习。[Ca2+]i升高通常以重复性钙尖峰或振荡的形式出现。由电刺激或受体刺激诱导，这些重复性钙尖峰随着受体刺激的幅度增加其频率，这一现象对于诱导选择性细胞功能似乎至关重要。在此，我们报告了RASAL的特性，RASAL是一种Ras GTP酶激活蛋白，通过与质膜进行同步振荡结合来感知重复性钙尖峰的频率。重要的是，我们表明只有在质膜结合期间，RASAL才会使Ras信号失活。因此，RASAL感知复杂钙信号的频率，通过调节Ras的激活状态对其进行解码。我们的数据揭示了复杂钙信号与Ras调节之间迄今未被认识的联系。
