ACTION POTENTIAL-DEPENDENT REGULATION OF GENE-EXPRESSION - TEMPORAL SPECIFICITY IN CA2-RESPONSIVE ELEMENT-BINDING PROTEINS, AND MITOGEN-ACTIVATED PROTEIN-KINASE SIGNALING( CAMP)

Specific patterns of neural impulses regulate genes controlling nervou s system development and plasticity, but it is not known how intracell ular signaling cascades and transcriptional activation mechanisms can regulate specific genes in response to specific patterns of action pot entials. Studies using electrical stimulation of mouse dorsal root gan glion neurons in culture show that the temporal dynamics of intracellu lar signaling pathways are an important factor, Expression of c-fos va ried inversely with the interval between repeated bursts of action pot entials, Transcription was not dependent on a large or sustained incre ase in intracellular Ca2+, and high Ca2+ levels separated by long inte rburst intervals (5 min) produced minimal increases in c-fos expressio n. Levels of the transcription factor cAMP-responsive element binding protein (CREB), phosphorylated at Ser-133, increased rapidly in respon se to brief action potential stimulation but remained at high levels s everal minutes after an action potential burst. These kinetics limited the fidelity with which P-CREB could follow different patterns of act ion potentials, and P-CREB levels were not well correlated with c-fos expression, The extracellular-regulated kinase (ERK) mitogen-activated protein kinases (MAPK) also were stimulated by action potentials of a ppropriate temporal patterns, Bursts of action potentials separated by long intervals (5 min) did not activate MAPK effectively, but they di d increase CREB phosphorylation. This was a consequence of the more ra pid dephosphorylation of MAPK in comparison to CREB, High expression o f c-fos was dependent on the combined activation of the MAPK pathway a nd phosphorylation of CREB, These observations show that temporal feat ures of action potentials (and associated Ca2+ transients) regulate ex pression of neuronal genes by activating specific intracellular signal ing pathways with appropriate temporal dynamics.