Identification of a Ras GTPase-activating protein regulated by receptor-mediated Ca(2+) oscillations

Abstract

Receptor-mediated increases in the concentration of intracellular free calcium ([Ca(2+)](i)) are responsible for controlling a plethora of physiological processes including gene expression, secretion, contraction, proliferation, neural signalling, and learning. Increases in [Ca(2+)](i) often occur as repetitive Ca(2+) spikes or oscillations. Induced by electrical or receptor stimuli, these repetitive Ca(2+) 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 Ca(2+) 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 Ca(2+) signals, decoding them through a regulation of the activation state of Ras. Our data provide a hitherto unrecognised link between complex Ca(2+) signals and the regulation of Ras