The frequencies of calcium oscillations are optimized for efficient calcium-mediated activation of Ras and the ERK/MAPK cascade

Abstract

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 ( [Ca 2ϩ ] i is responsible for controlling a diverse array of cellular processes, including secretion, contraction, learning, and proliferation (3). Understanding how receptor-mediated increases in [Ca 2ϩ ] i are capable of modulating so many physiological processes is one of the major challenges in the study of Ca 2ϩ signaling. It appears that such control is achieved through a complex relationship between the amplitude and spatiotemporal patterning of the Ca 2ϩ signal and its resultant ability to couple to an extensive molecular repertoire of Ca 2ϩ -sensing proteins (3).Receptor-mediated increases in [Ca 2ϩ ] i are often observed as repetitive Ca 2ϩ spikes or oscillations that increase their frequency with the amplitude of the receptor stimuli (refs. 4 and 5; reviewed in ref. 3). These frequency-encoded signals appear to be critical for the induction of selective cellular functions (3). For example, the frequency of receptor-mediated Ca 2ϩ oscillations determines the efficiency of gene expression driven by the transcription factors NF-AT, OAP, and NF-B (6-8) and mitochondrial ATP production (9). To decode the information contained within Ca 2ϩ oscillations, cells have evolved a number of frequency-modulated decoders. Such proteins include calmodulin (10), protein kinase C (11-15), calpain (16), calmodulin-dependent protein kinase II (17,18), and the Ras GTPaseactivating protein RASAL (19).Ras proteins are binary molecular switches that regulate multiple signaling pathways, including those controlling growth and differentiation, through an ability to cycle between inactive GDP-and active GTP-bound conformations (20-23). The magnitude and duration of Ras signaling is controlled by two classes of proteins: Guanine nucleotide exchange factors modulate Ras activation by enhancing the exchange of GDP for GTP, and GTPase-activating proteins regulate inactivation by increasing the intrinsic Ras GTPase activity (20-23). Although it has been known for some time that increases in [Ca 2ϩ ] i can modulate Ras activation (for example, Ca 2ϩ influx through voltage-operated ion channels or release from internal stores can activate Ras in neuronal cells) (24), only recently have molecular entities been described that allow for this coupling (reviewed in ref. 25).Two families of Ras guanine nucleotide exchange factors (GEFs), and RasGRPs (30-36), the latter also being known as CalDAG-GEFs, are modulated by increases in [Ca 2ϩ ] i . For RasGRFs, this modulation occurs indirectly through association with Ca 2ϩ ͞calmodulin, whereas for RasGRPs, a more direct control is achieved through association of Ca 2ϩ with atypical EF hands (25). In addition to stimulating Ras activation, increases in [Ca 2ϩ ] i ...

Purinergic signalling is required for calcium oscillations in migratory chondrogenic progenitor cells

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Estrogen Signaling Multiple Pathways to Impact Gene Transcription

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