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This Article Full Text Full Text (PDF) All Versions of this Article: 576/2/403    most recent jphysiol.2006.115295v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lancaster, B. Articles by Storm, J. F. Search for Related Content PubMed PubMed Citation Articles by Lancaster, B. Articles by Storm, J. F. Related Collections Cellular

¹ Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK
² Department of Physiology, Institute of Basal Medical Sciences, and Centre for Molecular Biology and Neuroscience, University of Oslo, PB 1103, Blindern, N-0317 Oslo, Norway

Ion channel regulation by cyclic AMP and protein kinase A is a major effector mechanism for monoamine transmitters and neuromodulators in the CNS. Surprisingly, there is little information about the speed and kinetic limits of cAMP–PKA-dependent excitability changes in the brain. To explore these questions, we used flash photolysis of caged-cAMP (DMNB-cAMP) to provide high temporal resolution. The resultant free cAMP concentration was calculated from separate experiments in which this technique was used, in excised patches, to activate cAMP-sensitive cyclic nucleotide-gated (CNG) channels expressed in Xenopus oocytes. In hippocampal pyramidal neurones we studied the modulation of a potassium current (slow AHP current, I_sAHP) known to be targeted by multiple transmitter systems that use cAMP–PKA. Rapid cAMP elevation by flash photolyis of 200 µM DMNB-cAMP completely inhibited the K⁺ current. The estimated yield (1.3–3%) suggests that photolysis of 200 µM caged precursor is sufficient for full PKA activation. By contrast, extended gradual photolysis of 200 µM DMNB-cAMP caused stable but only partial inhibition. The kinetics of rapid cAMP inhibition of the K⁺ conductance (time constant 1.5–2 s) were mirrored by changes in firing patterns commencing within 500 ms of rapid cAMP elevation. Maximal increases in firing were short-lasting (< 60 s) and gave way to moderately enhanced levels of spiking. The results demonstrate how the fidelity of phasic monoamine signalling can be preserved by the cAMP–PKA pathway.

(Received 12 June 2006; accepted after revision 3 August 2006; first published online 10 August 2006)
Corresponding author B. Lancaster: Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK. Email: b.lancaster{at}ucl.ac.uk

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