Cyclic nucleotide-gated channels contribute to the cholinergic plateau potential in hippocampal CA1 pyramidal neurons.
Plateau potentials are prolonged membrane depolarizations that are observed in hippocampal pyramidal neurons when spiking and Ca(2+) 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 Ca(2+) influx elicited a prolonged tail current (I(tail)) that had an extrapolated reversal potential of -20 mV. I(tail) was not observed when intracellular Ca(2+) 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 Ca(2+) 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.
Kuzmiski
J B
JB
Neuroscience Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
MacVicar
B A
BA
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018721:Muscarinic Agonists / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*
D002614:Chelating Agents; D054815:Cyclic Nucleotide-Gated Cation Channels; D004791:Enzyme Inhibitors; D007473:Ion Channels; D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D004533:Egtazic Acid; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium