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The Journal of Neuroscience, September 1, 2001, 21(17):6694-6705

Spike Frequency Decoding and Autonomous Activation of Ca²⁺-Calmodulin-Dependent Protein Kinase II in Dorsal Root Ganglion Neurons

Feleke Eshete and R. Douglas Fields

National Institutes of Health, National Institute of Child Health and Human Development, Bethesda, Maryland 20892-4480

Autonomous activation of calcium-calmodulin kinase (CaMKII) has been proposed as a molecular mechanism for decoding Ca²⁺ spike frequencies resulting from action potential firing, but this has not been investigated in intact neurons. This was studied in mouse DRG neurons in culture using confocal measurements of [Ca²⁺]_i and biochemical measurements of CaMKII autophosphorylation and autonomous activity. Using electrical stimulation at different frequencies, we find that CaMKII autonomous activity reached near maximal levels after ~45 impulses, regardless of firing frequency (1-10 Hz), and autonomous activity declined with prolonged stimulation. Frequency-dependent activation of CaMKII was limited to spike frequencies in the range of 0.1-1 Hz, despite marked increases in [Ca²⁺]_i at higher frequencies (1-30 Hz). The high levels of autonomous activity measured before stimulation and the relatively long duration of Ca²⁺ spikes induced by action potentials (~300 msec) are consistent with the lower frequency range of action potential decoding by CaMKII. The high autonomous activity under basal conditions was associated with extracellular [Ca²⁺], independently from changes in [Ca²⁺]_i, and unrelated to synaptic or spontaneous impulse activity. CaMKII autonomous activity in response to brief bursts of action potentials correlated better with the frequency of Ca²⁺ transients than with the concentration of [Ca²⁺]_i. In conclusion, CaMKII may decode frequency-modulated responses between 0.1 and 1 Hz in these neurons, but other mechanisms may be required to decode higher frequencies. Alternatively, CaMKII may mediate high-frequency responses in subcellular microdomains in which the enzyme is maintained at a low level of autonomous activity or the Ca²⁺ transients have faster kinetics.

Key words: Ca²⁺-calmodulin-dependent protein kinase II; autophosphorylation; Thr-286; frequency decoding; cytoplasmic calcium; extracellular calcium sensor; DRG neurons; CaMKII; LTP

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21176694-12$05.00/0

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