Small G proteins exhibit pattern sensitivity in MAPK activation during the induction of memory and synaptic facilitation in
            <i>Aplysia</i>

Ye, Xiaojing; Shobe, Justin L.; Sharma, Shiv K.; Marina, Andreea; Carew, Thomas

doi:10.1073/pnas.0808110105

Cited by 25 publications

(22 citation statements)

References 52 publications

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“…Pattern sensitivity in Aplysia sensorimotor long-term facilitations occurs at multiple levels, including G-proteins (Ye et al, 2008), temporal integration of PKA and MAPK signaling (Philips et al, 2013b), and PKA inhibition from increased PKC activity (Farah et al, 2009). An emerging principle from all of these studies is that pattern sensitivity arises from inhibitory interactions between signaling molecules involved in different forms of plasticity.…”

Section: Pattern Sensitivitymentioning

confidence: 99%

Sustained Hypoxia Elicits Competing Spinal Mechanisms of Phrenic Motor Facilitation

2016

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Acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF), a form of spinal motor plasticity. Competing mechanisms give rise to phrenic motor facilitation (pMF; a general term including pLTF) depending on the severity of hypoxia within episodes. In contrast, moderate acute sustained hypoxia (mASH) does not elicit pMF. By varying the severity of ASH and targeting competing mechanisms of pMF, we sought to illustrate why moderate AIH (mAIH) elicits pMF but mASH does not. Although mAIH elicits serotonindependent pLTF, mASH does not; thus, mAIH-induced pLTF is pattern sensitive. In contrast, severe AIH (sAIH) elicits pLTF through adenosine-dependent mechanisms, likely from greater extracellular adenosine accumulation. Because serotonin-and adenosinedependent pMF interact via cross talk inhibition, we hypothesized that pMF is obscured because the competing mechanisms of pMF are balanced and offsetting during mASH. Here, we demonstrate the following: (1) blocking spinal A 2A receptors with MSX-3 reveals mASHinduced pMF; and (2) sASH elicits A 2A -dependent pMF. In anesthetized rats pretreated with intrathecal A 2A receptor antagonist injections before mASH (PaO 2 ϭ 40 -54 mmHg) or sASH (PaO 2 ϭ 25-36 mmHg), (1) mASH induced a serotonin-dependent pMF and (2) sASH induced an adenosine-dependent pMF, which was enhanced by spinal serotonin receptor inhibition. Thus, competing adenosine-and serotonin-dependent mechanisms contribute differentially to pMF depending on the pattern/severity of hypoxia. Understanding interactions between these mechanisms has clinical relevance as we develop therapies to treat severe neuromuscular disorders that compromise somatic motor behaviors, including breathing. Moreover, these results demonstrate how competing mechanisms of plasticity can give rise to pattern sensitivity in pLTF.

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Section: Pattern Sensitivitymentioning

confidence: 99%

Sustained Hypoxia Elicits Competing Spinal Mechanisms of Phrenic Motor Facilitation

2016

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“…44 Thus, the activating or inhibitory effect of Rap1 on ERK signaling depends on the relative abundance of B-Raf and C-Raf found in a particular cell type. 25,26,45 B-Raf is expressed in megakaryocytes and platelets, and the B-Raf/Rap1 pathway was shown to stimulate the ERK cascade in a model of megakaryocyte differentiation. 46 C-Raf expression in platelets has also been demonstrated.…”

Section: Caldag-gefi In Platelet Calciummentioning

confidence: 99%

CalDAG-GEFI is at the nexus of calcium-dependent platelet activation

Stefanini

Roden

Bergmeier

2009

Blood

138

150

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The importance of the second messengers calcium (Ca 2؉ ) and diacylglycerol (DAG) in platelet signal transduction was established more than 30 years ago. Whereas protein kinase C (PKC) family members were discovered as the targets of DAG, little is known about the molecular identity of the main Ca 2؉ sensor(s). We here identify Ca 2؉ and DAG-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) as a critical molecule in Ca 2؉ -dependent platelet activation. CalDAG-GEFI, through activation of the small GTPase Rap1, directly triggers integrin activation and extracellular signalregulated kinase-dependent thromboxane A 2 (TxA 2 ) release. CalDAG-GEFIdependent TxA 2 generation provides crucial feedback for PKC activation and granule release, particularly at threshold agonist concentrations. PKC/P2Y12 signaling in turn mediates a second wave of Rap1 activation, necessary for sustained platelet activation and thrombus stabilization. Our results lead to a revised model for platelet activation that establishes one molecule, CalDAG-GEFI, at the nexus of Ca 2؉ -induced integrin activation, TxA 2 generation, and granule release. The preferential activation of CalDAG-GEFI over PKC downstream of phospholipase C activation, and the different kinetics of CalDAG-GEFI-and PKC/P2Y12-mediated Rap1 activation demonstrate an unexpected complexity to the platelet activation process, and they challenge the current model that DAG/PKC-dependent signaling events are crucial for the initiation of platelet adhesion. IntroductionPlatelet thrombus formation at sites of vascular injury is a complex and dynamic process that occurs in several phases. 1,2 Platelet preactivation and tethering (transient adhesion) are mediated by the interaction of glycoprotein (GP) lb␣ with matrix-bound von Willebrand factor, particularly in conditions of high shear. Platelet activation and firm adhesion are then triggered by collagen exposed in the vessel wall and/or locally generated thrombin. Sustained integrin activation and the formation of stable thrombi further depend on persistent costimulatory signaling provided by the second wave agonists, thromboxane A 2 (TxA 2 ) and adenosine 5Ј-diphosphate (ADP), which are released from activated platelets. [3][4][5] The central biochemical event in platelet aggregation is the agonist-induced inside-out activation of ␣ IIb ␤ 3 integrin. Most platelet agonists initiate intracellular signaling through the activation of phospholipase C (PLC), followed by the generation of the second messengers calcium (Ca 2ϩ ) and diacylgycerol (DAG). DAG is critical for protein kinase C (PKC) activation, a key event in platelet granule release and integrin activation. Platelets express at least 6 PKC isoforms, which have activating as well as inhibitory roles in platelet activation. [6][7][8][9][10] Early studies with calcium ionophores established a role of Ca 2ϩ in integrin activation, TxA 2 generation, and granule release. 11-13 Initially, Ca 2ϩ -binding classical isoforms of PKC were suggested as the cell's main signal integ...

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“…3,24 Moreover, the balance between Ras and Rap activities also seems to be a critical parameter, not merely their individual levels. 25 Thus, as discussed in further detail in the next section, our recent study 26 has sought to analyze Ras and Rap regulation in a more surgical manner via manipulation of specific Ras and Rap GAPs/GEFs. This approach has also allowed us to ask whether coordinated Ras/Rap signaling is important for one form of homeostatic plasticity, adaptation to chronic synaptic overexcitation.…”

Section: Introductionmentioning

confidence: 99%

Plk2 Raps up Ras to subdue synapses

2011

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We recently identified the activityinducible protein kinase Plk2 as a novel overseer of the balance between Ras and Rap small GTPases. Plk2 achieves a profound level of regulatory control by interacting with and phosphorylating at least four Ras and Rap guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Combined, these actions result in synergistic suppression of Ras and hyperstimulation of Rap signaling. Perturbation of Plk2 function abolished homeostatic adaptation of synapses to enhanced activity and impaired behavioral adaptation in various learning tasks, indicating that this regulation was critical for maintaining appropriate Ras/Rap levels. These studies provide insights into the highly cooperative nature of Ras and Rap regulation in neurons. However, different GEF and GAP substrates of Plk2 also controlled specific aspects of dendritic spine morphology, illustrating the ability of individual GAPs/GEFs to assemble microdomains of Ras and Rap signaling that respond to different stimuli and couple to distinct output pathways.

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Small G proteins exhibit pattern sensitivity in MAPK activation during the induction of memory and synaptic facilitation in Aplysia

Cited by 25 publications

References 52 publications

Sustained Hypoxia Elicits Competing Spinal Mechanisms of Phrenic Motor Facilitation

Sustained Hypoxia Elicits Competing Spinal Mechanisms of Phrenic Motor Facilitation

CalDAG-GEFI is at the nexus of calcium-dependent platelet activation

Plk2 Raps up Ras to subdue synapses

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