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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 (I_tail) that had an extrapolated reversal potential of 20 mV. I_tail was not observed when intracellular Ca²⁺ levels were chelated with 10 mM intracellular BAPTA, and I_tail was reversibly depressed in low external sodium. When I_tail was evoked at intervals >3 min, current amplitudes were stable for up to 1 hr. However, at shorter intervals, I_tail 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 I_tail and zaprinast, which blocks cGMP-specific phosphodiesterase, enhanced I_tail, suggesting that a component of I_tail was activated by cGMP. The inhibitors of cyclic nucleotide-gated (CNG) channels L-cis-diltiazem and 2',4'-dichlorobenzamil reversibly depressed I_tail. However, protein kinase G inhibition had no effect. Therefore, these results indicate that a component of I_tail 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

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21228707-08$05.00/0

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