The Frequencies of Calcium Oscillations Are Optimized for Efficient Calcium-Mediated Activation of Ras and the ERK/MAPK Cascade

Ras proteins are binary switches that, by cycling through inactive GDP- and active GTP-bound conformations, regulate multiple cellular signaling pathways, including those that control growth and differentiation. For some time, it has been known that receptormediated increases in the concentration of intracellular free calcium ([ Ca2+] i) can modulate Ras activation. Increases in [ Ca2+] i often occur as repetitive Ca2+ spikes or oscillations. Induced by electrical or receptor stimuli, these repetitive Ca2+ oscillations increase in frequency with the amplitude of receptor stimuli, a phenomenon critical for the induction of selective cellular functions. Here, we show that Ca2+ oscillations are optimized for Ca2+-mediated activation of Ras and signaling through the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cascade. We present additional evidence that Ca2+ oscillations reduce the effective Ca2+ threshold for the activation of Ras and that the oscillatory frequency is optimized for activation of Ras and the ERK/MAPK pathway. Our results describe a hitherto unrecognized link between complex Ca2+ signals and the modulation of the Ras/ERK/MAPK signaling cascade.