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Molecular and Cellular Biology, July 2003, p. 4788-4795, Vol. 23, No. 14
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.14.4788-4795.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Temporal Characteristics of Activation, Deactivation, and Restimulation of Signal Transduction following Depolarization in the Pheochromocytoma Cell Line PC12

Amir H. Nashat and Robert Langer*

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Received 4 February 2003/ Accepted 3 April 2003

This study focuses on the transient and dynamic activation of intracellular signal transduction following different protocols of depolarization. During chronic depolarization, phosphorylation of extracellular signal-regulated kinases (ERKs) was observed to peak and subsequently fall to low levels within 10 min of depolarization. Short periods of depolarization, from 1 to 5 min in duration, also led to phosphorylation of ERK, and the rate of ERK dephosphorylation was not affected by the duration of depolarization. Phosphorylation of the cyclic AMP response element binding protein (CREB) also peaked as a result of chronic depolarization but decreased to intermediate levels that were maintained for more than 1 h. Pulsatile depolarization was explored as a means to circumvent the deactivation of intracellular signaling activity during chronic depolarization. Both ERK and CREB were rephosphorylated by a second period of depolarization that followed a recovery period of 10 min or more. The effects of the durations of depolarization and interpulse recovery on reactivation of ERK and CREB were characterized. Measurements of free cytoplasmic Ca2+ confirmed the transient rise in the intracellular calcium concentration ([Ca2+]i) during chronic depolarization and the pulsatile increase in [Ca2+]i that can be achieved with short periods of depolarization. This study characterizes the dynamic activities of signal transduction following depolarization. Electrical stimulation of neurons induces many cellular changes that unfold over time, and the influx of Ca2+ ions that mediate these events is transient. This study suggests that pulsatile activity may be a means of maintaining signaling activity over long periods of time.

* Corresponding author. Mailing address: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. Phone: (617) 253-3107. Fax: (617) 258-8827. E-mail: rlanger{at}mit.edu.

Molecular and Cellular Biology, July 2003, p. 4788-4795, Vol. 23, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.14.4788-4795.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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