The Journal of Neuroscience, November 15, 2001, 21(22):8707-8714
Cyclic Nucleotide-Gated Channels Contribute to the Cholinergic
Plateau Potential in Hippocampal CA1 Pyramidal Neurons
J. Brent
Kuzmiski and
Brian A.
MacVicar
Neuroscience Research Group, Department of Physiology and
Biophysics, University of Calgary, Calgary, Alberta T2N 4N1,
Canada
Plateau potentials are prolonged membrane depolarizations that are
observed in hippocampal pyramidal neurons when spiking and
Ca2+ entry occur in combination with muscarinic
receptor activation. In this study, we used whole-cell voltage clamping
to study the current underlying the plateau potential and to determine
the cellular signaling pathways contributing to this current. When combined with muscarinic stimulation, depolarizing command potentials that evoked Ca2+ influx elicited a prolonged tail
current (Itail) that had an extrapolated reversal potential of 
20 mV.
Itail was not observed when intracellular
Ca2+ levels were chelated with 10 mM
intracellular BAPTA, and Itail was
reversibly depressed in low external sodium. When
Itail was evoked at intervals >3 min,
current amplitudes were stable for up to 1 hr. However, at shorter
intervals, Itail was refractory, with a time
constant of recovery of 43.5 sec. The inhibitors of soluble guanylate
cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one and
6-anilino-5,8-quinolinequinone depressed
Itail and zaprinast, which blocks
cGMP-specific phosphodiesterase, enhanced
Itail, suggesting that a component of
Itail was activated by cGMP. The inhibitors
of cyclic nucleotide-gated (CNG) channels
L-cis-diltiazem and 2',4'-dichlorobenzamil
reversibly depressed Itail. However, protein
kinase G inhibition had no effect. Therefore, these results indicate
that a component of Itail is
attributable to activation of CNG channels. We conclude that
Ca2+ influx when combined with muscarinic receptor
activation activates soluble guanylate cyclase and increases cGMP
levels. The increased cGMP activates CNG channels and leads to
prolonged depolarization. The cation conductance of the CNG channel
contributes to the prolonged depolarization of the plateau potential.
Key words:
seizure; acetylcholine; muscarinic receptors; cGMP; guanylate cyclase; hippocampus; epilepsy
Copyright © 2001 Society for Neuroscience 0270-6474/01/21228707-08$05.00/0
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