PIP2 hydrolysis is responsible for voltage independent inhibition of CaV2.2 channels in sympathetic neurons

Vivas, Oscar; Castro, Héctor; Arenas, Isabel; Elı́as-Viñas, David; García, David

doi:10.1016/j.bbrc.2013.01.117

Cited by 26 publications

(36 citation statements)

References 39 publications

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“…We have found evidence that voltage-gated Na 1 channels may be also modulated in a slow manner by a diffusible second messenger (Hernández-Ochoa et al, 2007). In a recent study, we showed that M1 receptor activation inhibits Ca V 2.2 channels in a voltage-independent manner by a slowly activating pathway (Vivas et al, 2013). These observations prompted us to study a general mechanism in which muscarinic activation also modulates I Na through a diffusible cytoplasmic second messenger.…”

Section: M1 Receptor Activation Elicited a Voltage-independentmentioning

confidence: 96%

“…Increasing evidence shows that slow modulation of calcium channels requires phosphatidylinositol 4,5-bisphosphate (PIP 2 ) (Suh et al, 2010). Recently, we showed evidence that PIP 2 is the molecule responsible for the voltage-insensitive inhibition of Ca V 2.2 channels (Vivas et al, 2013). In addition, we showed that all Gb subunits exhibit a differential voltageinsensitive component (Hernández-Castellanos et al, 2014).…”

Section: Introductionmentioning

confidence: 94%

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Voltage-Independent Inhibition of the Tetrodotoxin-Sensitive Sodium Currents by Oxotremorine and Angiotensin II in Rat Sympathetic Neurons

et al. 2016

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Tetrodotoxin-sensitive Na 1 currents have been extensively studied because they play a major role in neuronal firing and bursting. In this study, we showed that voltage-dependent Na 1 currents are regulated in a slow manner by oxotremorine (oxo-M) and angiotensin II in rat sympathetic neurons. We found that these currents can be readily inhibited through a signaling pathway mediated by G proteins and phospholipase C (PLC) b1. This inhibition is slowly established, pertussis toxin-insensitive, partially reversed within tens of seconds after oxo-M washout, and not relieved by a strong depolarization, suggesting a voltageinsensitive mechanism of inhibition. Specificity of the M1 receptor was tested by the MT-7 toxin. Activation and inactivation curves showed no shift in the voltage dependency under the inhibition by oxo-M. This inhibition is blocked by a PLC inhibitor (U73122, 1-(6-{[(17b)-3-Methoxyestra-1,3,5(10)-trien-17-yl]amino}hexyl)-1H-pyrrole-2,5-dione), and recovery from inhibition is prevented by wortmannin, a PI3/4 kinase inhibitor. Hence, the pathway involves G q/11 and is mediated by a diffusible second messenger. Oxo-M inhibition is occluded by screening phosphatidylinositol 4,5-bisphosphate (PIP 2 )-negative charges with poly-L-lysine and prevented by intracellular dialysis with a PIP 2 analog. In addition, bisindolylmaleimide I, a specific ATP-competitive protein kinase C (PKC) inhibitor, rules out that this inhibition may be mediated by this protein kinase. Furthermore, oxo-M-induced suppression of Na 1 currents remains unchanged when neurons are treated with calphostin C, a PKC inhibitor that targets the diacylglycerolbinding site of the kinase. These results support a general mechanism of Na 1 current inhibition that is widely present in excitable cells through modulation of ion channels by specific G protein-coupled receptors.

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Section: M1 Receptor Activation Elicited a Voltage-independentmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 94%

Voltage-Independent Inhibition of the Tetrodotoxin-Sensitive Sodium Currents by Oxotremorine and Angiotensin II in Rat Sympathetic Neurons

et al. 2016

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“…Because the expression of  subunits varies spatially and temporally in brain tissues [21, 22, 24,26,[37][38][39][40][41][42] , CaV2.2 modulation by GqPCRs can also be gradated. Hereby, our research proposes a novel GqPCR-mediated signaling pathway for CaV2.2 channel modulation that extends previous observations that CaV channels can be regulated by multiple signals [43][44][45][46] …”

Section: Research Highlightmentioning

confidence: 99%

Section: Research Highlightmentioning

confidence: 99%

“…The role of the G subunit in GqPCR modulation of CaV2.2 channels remains unclear. It is possible that the G subunit released from the Gq/11 protein can produce fast and voltage-dependent inhibition of the CaV2.2 current [21, 22,[24][25][26] .Previous studies have revealed that the slow component of CaV2.2 channel modulation by the Gq/11-coupled M1 muscarinic acetylcholine receptor (M1R) relies on PIP2 depletion through Gαq/PLC activation and that the CaV subunit is an important regulator of the muscarinic modulation of the channel [13, 22] . Indeed, since GqPCRs activation accompanies many downstream signals, such as Ca 2+ release from the endoplasmic reticulum and PKC activation via diacylglycerol generation, discriminating between PIP2 effects and those of other signals is almost impossible.…”

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confidence: 99%

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Molecular basis for N-type voltage-gated Ca2+ channel modulation by Gq protein-coupled receptors

Keum

Suh

2015

Receptor Clin Invest

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N-type voltage-gated Ca2+ (CaV2.2) channels, which enable synaptic transmission by triggering neurotransmitter release, are tightly modulated by G protein-coupled receptors (GPCRs) via several downstream signaling messengers, such as G, calmodulin, arachidonic acid and PIP2. However, the molecular mechanism by which Gq/11-coupled receptors (GqPCRs) suppress CaV2.2 currents remains unclear. In this research highlight, we review our recent finding that M1 muscarinic receptors inhibit CaV2.2 channels through both G-mediated voltage-dependent (VD) and Gαq/11/PLC-mediated voltage-independent (VI) pathways. Our photometry results also demonstrate that G-mediated VD inhibition of CaV2.2 channels initiates approximately 3 s earlier than VI inhibition, and is strongly potentiated in cells expressing plasma membrane-localized CaV subunits. Our observations demonstrate a novel mechanism for CaV2.2 channel modulation by GqPCRs where the subcellular location of CaV subunits plays a critical role in determining the voltage-dependence of current suppression by M1 receptors. [1] in response to the propagation of electrical stimulations and to the processes it underlies, such as learning and memory [2] and gene transcription [3] . CaV2.2 channels are widely expressed throughout the brain [4] and spinal cord [5] , and knockout mice who lack CaV2.2 channels show cardiovascular impairment [6] , hyperactivity [7] , reduced alcohol consumption [8] , and hyperaggressive behavior [9] . The biophysical and pharmacological properties of CaV2.2 channels are determined by diverse combinations of channel subunits. CaVα1B and CaVα2δ are transmembrane proteins. CaVα1B subunits are responsible for forming the voltage-sensitive pore of the channel and CaVα2δ subunits are responsible for promoting CaVα1 subunit stabilization at the plasma membrane [10] . CaV subunits are intracellular components that play an essential role in regulating the gating properties and receptor modulation of CaV channels. They bind to the I-II linker of the CaVα1 subunit and finely tune the trafficking of α1 channel proteins to the plasma membrane, current density, channel inactivation and channel regulation by phospholipids [11][12][13][14] . KeywordsG-protein coupled receptors (GPCRs) precisely regulate Ca 2+ ion influx through CaV2.2 channels [15,16] . The activation of GPCRs coupled to Gαi/o (Gi/oPCRs) or Gαq/11 (GqPCRs) is known to suppress CaV2.2 current through two distinct pathways. The first operates via G heterodimer dissociation from Gi/oPCR. The G heterodimer then directly binds to the I-II linker of the CaVα1B subunit, which partially overlaps with the binding site of the CaV subunit, RESEARCH HIGHLIGHTReceptors & Clinical Investigation 2015; 2: e515. doi: 10.14800/rci.515; © 2015 by Dongil Keum, et al.Page 2 of 5 and triggers fast current inhibition [17] . Since the G binding to the α1B subunit slows channel activation and shifts the voltage dependence of the channel opening towards a positive charge, a stronger depolarization of the plas...

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Subunit Architecture and Atomic Structure of Voltage-Gated Ca2+ Channels

Catterall

2022

Voltage-Gated Calcium Channels

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PIP2 hydrolysis is responsible for voltage independent inhibition of CaV2.2 channels in sympathetic neurons

Cited by 26 publications

References 39 publications

Voltage-Independent Inhibition of the Tetrodotoxin-Sensitive Sodium Currents by Oxotremorine and Angiotensin II in Rat Sympathetic Neurons

Voltage-Independent Inhibition of the Tetrodotoxin-Sensitive Sodium Currents by Oxotremorine and Angiotensin II in Rat Sympathetic Neurons

Molecular basis for N-type voltage-gated Ca2+ channel modulation by Gq protein-coupled receptors

Subunit Architecture and Atomic Structure of Voltage-Gated Ca2+ Channels

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