Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone

Brown, David A.; Adams, Patrick W.

doi:10.1038/283673a0

Cited by 1,353 publications

(981 citation statements)

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“…Sources include the sodium-potassium pump, which produces a slow afterhyperpolarization (Gulledge et al 2013), channel mechanisms from different systems (Fleidervish et al 1996;Madison and Nicoll 1984;Brown and Adams 1980), and several general models (Benda and Herz 2003;Brette and Gerstner 2005). However, further research is necessary to determine their applicability to type I SGNs.…”

Section: Spike Rate Adaptationmentioning

confidence: 99%

Temporal Considerations for Stimulating Spiral Ganglion Neurons with Cochlear Implants

Boulet

White

Bruce

2015

JARO

103

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A wealth of knowledge about different types of neural responses to electrical stimulation has been developed over the past 100 years. However, the exact forms of neural response properties can vary across different types of neurons. In this review, we survey four stimulus-response phenomena that in recent years are thought to be relevant for cochlear implant stimulation of spiral ganglion neurons (SGNs): refractoriness, facilitation, accommodation, and spike rate adaptation. Of these four, refractoriness is the most widely known, and many perceptual and physiological studies interpret their data in terms of refractoriness without incorporating facilitation, accommodation, or spike rate adaptation. In reality, several or all of these behaviors are likely involved in shaping neural responses, particularly at higher stimulation rates. A better understanding of the individual and combined effects of these phenomena could assist in developing improved cochlear implant stimulation strategies. We review the published physiological data for electrical stimulation of SGNs that explores these four different phenomena, as well as some of the recent studies that might reveal the biophysical bases of these stimulus-response phenomena.

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Section: Spike Rate Adaptationmentioning

confidence: 99%

Temporal Considerations for Stimulating Spiral Ganglion Neurons with Cochlear Implants

Boulet

White

Bruce

2015

JARO

103

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“…118,119 In addition, mice in which a single copy of the gene for KCNQ2 was disrupted by gene targeting (Kcnq2 ϩ/Ϫ ) showed increased sensitivity to PTZ seizures. 120 The combination of KCNQ2 and KCNQ3 underlies the bulk of the Mcurrent in neurons, 121 although KCNQ5 alone or in combination with KCNQ3 can also contribute to M-current. It is believed that M-current regulates neuronal excitability by determining the neuronal firing threshold, influencing the firing rate, and modulating neuronal responsiveness to synaptic inputs.…”

Section: Voltage-gated Potassium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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“…Our RNAi/rescue approach was used to examine a second AKAP79/150-mediated event: the suppression of 'M current', a K + conductance that negatively regulates neuronal excitability in a variety of brain regions 18,19 . Muscarinic agonists inhibit this channel via a G q -coupled pathway that evokes phosphoinositide turnover 20,21 (Fig.…”

Section: Akap150 Coordinates Muscarinic Suppression Of M Currentsmentioning

confidence: 99%

Section: Akap150 Coordinates Muscarinic Suppression Of M Currentsmentioning

confidence: 99%

“…PKC phosphorylation of Ser 534 and Ser 541 on the KCNQ2 channel subunit has been implicated in the suppression of recombinant M currents 10 . The net result is a hyperexcitability of neurons because firing of action potentials is favoured when M currents are suppressed 18,19 .AKAP79-silenced HEK293 cells expressing a KCNQ2 subunit, a core component of the M current, showed reduced muscarinic inhibition by acetylcholine (see Supplementary Information, Fig. S1).…”

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Distinct enzyme combinations in AKAP signalling complexes permit functional diversity

2005

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Specificity in cell signalling can be influenced by the targeting of different enzyme combinations to substrates. The A-kinase anchoring protein AKAP79/150 is a multivalent scaffolding protein that coordinates the subcellular localization of second-messenger-regulated enzymes, such as protein kinase A, protein kinase C and protein phosphatase 2B. We developed a new strategy that combines RNA interference of the endogenous protein with a protocol that selects cells that have been rescued with AKAP79/150 forms that are unable to anchor selected enzymes. Using this approach, we show that AKAP79/150 coordinates different enzyme combinations to modulate the activity of two distinct neuronal ion channels: AMPA-type glutamate receptors and M-type potassium channels. Utilization of distinct enzyme combinations in this manner provides a means to expand the repertoire of cellular events that the same AKAP modulates.Cellular regulation must be accomplished through the synchronized actions of a limited number of gene products, as the number of mammalian genes that are required to sustain life is significantly less than was originally anticipated 1,2 . Signal-transduction pathways are created when enzymes, often with broad substrate specificities, act sequentially to evoke cellular responses 3 . Restricting the subcellular localization of these enzymes with scaffolding proteins contributes to the fidelity of each response 4 . Prototypic examples of these are the A-kinase anchoring proteins (AKAPs) that target the cyclic-AMP-dependent protein kinase (protein kinase A, PKA) and other enzymes to defined subcellular locations 5 .AKAP signalling complexes often include signal-transduction and signal-termination enzymes to regulate the forward and backward steps of a given process. The notion of multivalent anchoring proteins was first proposed for the AKAP79 family, which consists of a group of three structurally similar orthologues: human AKAP79, murine AKAP150 and bovine AKAP75 (ref. 6). These AKAPs contain binding sites for PKA, the calcium/ phospholipid-dependent kinase (protein kinase C, PKC) and the calcium/calmodulindependent phosphatase (protein phosphatase 2B, PP2B) 7 . They are tethered to the inner face of the plasma membrane, where they can respond to the generation of second messengers, such as cAMP, calcium and phospholipid 7 . Functional studies have shown that this AKAP family controls the phosphorylation status and action of several ion channels, including AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors, L-type calcium channels, aquaporin water channel, and M-type potassium channels [8][9][10] . One theory that accounts for this diversity of action is that unique combinations of anchored enzymes are recruited to individual ion channels. We tested this hypothesis in cells in which the endogenous anchoring protein was silenced and replaced with AKAP forms that were unable to anchor selected binding partners. Results Functional characterization of AKAP79-depleted cellsPl...

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Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone

Cited by 1,353 publications

References 10 publications

Temporal Considerations for Stimulating Spiral Ganglion Neurons with Cochlear Implants

Temporal Considerations for Stimulating Spiral Ganglion Neurons with Cochlear Implants

Molecular Targets for Antiepileptic Drug Development

Distinct enzyme combinations in AKAP signalling complexes permit functional diversity

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