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Kinetics of ion channel modulation by cAMP in rat hippocampal neurones

2006; Wiley; Volume: 576; Issue: 2 Linguagem: Inglês

10.1113/jphysiol.2006.115295

1469-7793

Barrie Lancaster, Hua Hu, Barry Gibb, Johan F. Storm,

Phosphodiesterase function and regulation

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 μ m DMNB‐cAMP completely inhibited the K + current. The estimated yield (1.3–3%) suggests that photolysis of 200 μ m caged precursor is sufficient for full PKA activation. By contrast, extended gradual photolysis of 200 μ m 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.