Recovery from Muscarinic Modulation of M Current Channels Requires Phosphatidylinositol 4,5-Bisphosphate Synthesis

Suh, Byung‐Chang; Hille, Bertil

doi:10.1016/s0896-6273(02)00790-0

Cited by 447 publications

(517 citation statements)

References 53 publications

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“…Activation of GIRK channels requires permissive levels of membrane PIP 2 and increased channel activity results from Gβγ-mediated stabilization of PIP 2 -GIRK binding (Huang et al, 1998, Zhang et al, 1999. In fact, the regulation of channel activities by Gβγ, PIP 2 , or phosphorylation occurs on the time scale of a few seconds which can be resolved by electrophysiological techniques (Suh and Hille, 2002). In recent studies from our lab we have found that PI3K plays a critical role in facilitating the rapid membrane response to estrogen, as elucidated by the use of PI3K inhibitors (Malyala et al, 2008).…”

Section: Effects Of 17β -Estradiol On Vmh and Arcuate Neurons: Role Imentioning

confidence: 99%

Membrane-initiated estrogen signaling in hypothalamic neurons

Kelly

Rønnekleiv

2008

Molecular and Cellular Endocrinology

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SummaryIt is well known that many of the actions of 17β-estradiol (E2) in the central nervous system are mediated via intracellular receptor/transcription factors that interact with steroid response elements on target genes. However, there is compelling evidence for membrane steroid receptors for estrogen in hypothalamic and other brain neurons. But it is not well understood how estrogen signals via membrane receptors, and how these signals impact not only membrane excitability but also gene transcription in neurons. Indeed, it has been known for sometime that E2 can rapidly alter neuronal activity within seconds, indicating that some cellular effects can occur via membrane delimited events. In addition, E2 can affect second messenger systems including calcium mobilization and a plethora of kinases to alter cell signaling. Therefore, this review will consider our current knowledge of rapid membrane-initiated and intracellular signaling by E2 in the hypothalamus, the nature of receptors involved and how they contribute to homeostatic functions. KeywordsERα; ERβ; GPCR (G protein-coupled receptor); mER (membrane estrogen receptor that is a GPCR) Electrophysiological studies in the 1960's and 1970's suggested that gonadal steroids could directly modulate the electrical activity of hypothalamic neurons

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Section: Effects Of 17β -Estradiol On Vmh and Arcuate Neurons: Role Imentioning

confidence: 99%

Membrane-initiated estrogen signaling in hypothalamic neurons

Kelly

Rønnekleiv

2008

Molecular and Cellular Endocrinology

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“…Muscarinic agonists inhibit this channel via a G q -coupled pathway that evokes phosphoinositide turnover 20,21 (Fig. 6a).…”

Section: Akap150 Coordinates Muscarinic Suppression Of M Currentsmentioning

confidence: 99%

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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“…First, Li þ inhibits several cellular enzymes involved in inositol recycling, a crucial step in the synthesis of the PIP2, 43 a membrane phospholipid that is essential for KCNQ2 activity and for its regulation by acetylcholine as well as by other neurotransmitters and peptides. [44][45][46] Li þ by interfering with this pathway of regulation will necessarily interfere with KCNQ2 activity either basic or regulated by neurotransmitters such as acetylcholine acting on the M1 receptor. Second, the kinase GSK3b has also been shown to be inhibited by Li þ 43,47 and we have shown in this paper that GSK3b can, in vitro, phosphorylate KCNQ2 and that this phosphorylation is decreased by Li þ .…”

Section: Pp2a-bc and Kcnq2 In Bipolar Diseasementioning

confidence: 99%

PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder

Borsotto

Cavarec²,

Bouillot³

et al. 2006

Pharmacogenomics J

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Many bipolar affective disorder (BD) susceptibility loci have been identified but the molecular mechanisms responsible for the disease remain to be elucidated. In the locus 4p16, several candidate genes were identified but none of them was definitively shown to be associated with BD. In this region, the PPP2R2C gene encodes the Bg-regulatory subunit of the protein phosphatase 2A (PP2A-Bg). First, we identified, in two different populations, single nucleotide polymorphisms and risk haplotypes for this gene that are associated to BD. Then, we used the Bg subunit as bait to screen a human brain cDNA library with the yeast two-hybrid technique. This led us to two new splice variants of KCNQ2 channels and to the KCNQ2 channel itself. This unusual K þ channel has particularly interesting functional properties and belongs to a channel family that is already known to be implicated in several other monogenic diseases. In one of the BD populations, we also found a genetic association between the KCNQ2 gene and BD. We show that KCNQ2 splice variants differ from native channels by their shortened C-terminal sequences and are unique as they are active and exert a dominant-negative effect on KCNQ2 wild-type (wt) channel activity. We also show that the PP2A-Bg subunit significantly increases the current generated by KCNQ2wt, a channel normally inhibited by phosphorylation. The kinase glycogen synthase kinase 3 beta (GSK3b) is considered as an interesting target of lithium, the classical drug used in BD. GSK3b phosphorylates the KCNQ2 channel and this phosphorylation is decreased by Li þ .

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Recovery from Muscarinic Modulation of M Current Channels Requires Phosphatidylinositol 4,5-Bisphosphate Synthesis

Cited by 447 publications

References 53 publications

Membrane-initiated estrogen signaling in hypothalamic neurons

Membrane-initiated estrogen signaling in hypothalamic neurons

Distinct enzyme combinations in AKAP signalling complexes permit functional diversity

PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder

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