title: Knockout of the BK β4-subunit promotes a functional coupling of BK channels and ryanodine receptors that mediate a fAHP-induced increase in excitability.
abstract: BK channels are large-conductance calcium- and voltage-activated potassium channels with diverse properties. Knockout of the accessory BK β4-subunit in hippocampus dentate gyrus granule neurons causes BK channels to change properties from slow-gated type II channels to fast-gated type I channels that sharpen the action potential, increase the fast afterhyperpolarization (fAHP) amplitude, and increase spike frequency. Here we studied the calcium channels that contribute to fast-gated BK channel activation and increased excitability of β4 knockout neurons. By using pharmacological blockers during current-clamp recording, we find that BK channel activation during the fAHP is dependent on ryanodine receptor activation. In contrast, L-type calcium channel blocker (nifedipine) affects the BK channel-dependent repolarization phase of the action potential but has no effect on the fAHP. Reducing BK channel activation during the repolarization phase with nifedipine, or during the fAHP with ryanodine, indicated that it is the BK-mediated increase of the fAHP that confers proexcitatory effects. The proexcitatory role of the fAHP was corroborated using dynamic current clamp. Increase or decrease of the fAHP amplitude during spiking revealed an inverse relationship between fAHP amplitude and interspike interval. Finally, we show that the seizure-prone ryanodine receptor gain-of-function (R2474S) knockin mice have an unaltered repolarization phase but larger fAHP and increased AP frequency compared with their control littermates. In summary, these results indicate that an important role of the β4-subunit is to reduce ryanodine receptor-BK channel functional coupling during the fAHP component of the action potential, thereby decreasing excitability of dentate gyrus neurons.
authors.affiliation: Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas; and.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas; and.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Bugay
authors.affiliation: Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas; and.
authors.forename: Ling
authors.initials: L
authors.lastname: Ling
authors.affiliation: Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas; and.
authors.forename: Hui-Hsui
authors.initials: HH
authors.lastname: Chuang
authors.affiliation: Department of Biology, University of Texas at San Antonio, San Antonio, Texas.
authors.forename: David B
authors.initials: DB
authors.lastname: Jaffe
authors.affiliation: Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas; and brennerr@uthscsa.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Brenner
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D001703:Biophysics; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018891:Dentate Gyrus / Q000166:cytology; D004558:Electric Stimulation; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000172:deficiency* / Q000235:genetics; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D007211:Indoles; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D026902:Potassium Channel Blockers; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; C048220:paxilline; D020866:omega-Conotoxin GVIA; D009543:Nifedipine
keywords: action potentials; dentate gyrus; fast afterhyperpolarization; large-conductance calcium- and voltage-activated potassium channels