Browsing by Author "Jarvis, Scott E."

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    AKAP79 modulation of L-type channels involves disruption of intramolecular interactions in the CaV1.2 subunit
    (Landes Bioscience, 2012-05) Altier, Christophe; Dubel, Stefan J.; Barrère, Christian; Jarvis, Scott E.; Stotz, Stephanie C.; Scott, John D.; Nargeot, Joël; Zamponi, Gerald W.; Bourinet, Emmanuel
    L-type voltage gated calcium channels (VGCCs) interact with a variety of proteins that modulate both their function and localization. A-Kinase Anchoring Proteins (AKAPs) facilitate L-type calcium channel phosphorylation through β adrenergic stimulation. Our previous work indicated a role of neuronal AKAP79/150 in the membrane targeting of Ca(V)1.2 L-type calcium channels, which involved a proline rich domain (PRD) in the intracellular II-III loop of the channel.(1) Here, we show that mutation of proline 857 to alanine (P857A) into the PRD does not disrupt the AKAP79-induced increase in Ca(v)1.2 membrane expression. Furthermore, deletion of two other PRDs into the carboxy terminal domain of Ca(V)1.2 did not alter the targeting role of AKAP79. In contrast, the distal carboxy terminus region of the channel directly interacts with AKAP79. This protein-protein interaction competes with a direct association of the channel II-III linker on the carboxy terminal tail and modulates membrane targeting of Ca(V)1.2. Thus, our results suggest that the effects of AKAP79 occur through relief of an autoinhibitory mechanism mediated by intramolecular interactions of Ca(v)1.2 intracellular regions.
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    Bipartite syntaxin 1A interactions mediate CaV2.2 calcium channel regulation
    (Elsevier, 2011-07-05) Davies, Jonathan N.; Jarvis, Scott E.; Zamponi, Gerald W.
    Functional interactions between syntaxin 1A and Ca(V)2 calcium channels are critical for fast neurotransmitter release in the mammalian brain, and coexpression of syntaxin 1A with these channels not only regulates channel availability, but also promotes G-protein inhibition. Both the syntaxin 1A C-terminal H3 domain, and N-terminal Ha domain have been shown to interact with the Ca(V)2.2 channel synprint region, suggesting a bipartite model of functional interaction, however the molecular determinants of this interaction have not been closely investigated. We used in vitro binding assays to assess interactions of syntaxin 1A truncation mutants with Ca(V)2.2 synprint and Ca(V)2.3 II-III linker regions. We identified two distinct interactions between the Ca(V)2.2 synprint region and syntaxin 1A: the first between C-terminal H3c domain of syntaxin 1A and residues 822-872 of Ca(V)2.2; and the second between the N-terminal 10 residues of the syntaxin 1A Ha region and residues 718-771 of Ca(V)2.2. The N-terminal syntaxin 1A fragment also interacted with the Ca(V)2.3 II-III linker. We then performed whole cell patch clamp recordings to test the effects of a putative interacting syntaxin 1A N-terminus peptide with Ca(V)2.2 and Ca(V)2.3 channels in a recombinant expression system. A YFP-tagged peptide corresponding to the N-terminal 10 residues of the syntaxin 1A Ha domain was sufficient to allosterically inhibit both Ca(V)2.2 and Ca(V)2.3 channel function but had no effect on G-protein mediated inhibition. Our results support a model of bipartite functional interactions between syntaxin 1A and Ca(V)2.2 channels and add accuracy to the two putative interacting domains, consistent with previous studies. Furthermore, we highlight the syntaxin 1A N-terminus as the minimal determinant for functional regulation of Ca(V)2.2 and Ca(V)2.3 channels.
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    The Mechanisms of Fatigability from Whole-Body Exercise and its Relationship to Chronic Fatigue in People with Multiple Sclerosis
    (2018-08-09) Coates, Kyla; Millet, Guillaume Y.; Culos-Reed, Susan Nicole; Zijdewind, Inge; Jarvis, Scott E.
    Objectives: The present study investigated the mechanisms of neuromuscular fatigue in people with Multiple Sclerosis (PwMS) during cycling to determine whether chronic perceived fatigue is associated with motor fatigability in PwMS. Methods: Thirteen PwMS with high levels of perceived fatigue (HF), thirteen PwMS with low levels of perceived fatigue (LF), and thirteen healthy controls (CON) completed an incremental cycling task to volitional exhaustion. By employing an innovative cycle ergometer, neuromuscular evaluations (NME) were performed at baseline, every 3 minutes during cycling, and immediately after exhaustion. Maximal voluntary contractions (MVC) and electrical stimulation of the femoral nerve (PNS) were used to quantify voluntary activation (VA) and muscle contractile ability (PT) of the knee extensors during each NME. The EMG responses to PNS (Mmax) and transcranial magnetic stimulation (MEP) during 50% of MVC were used to quantify central drive (EMG-RMS/Mmax), corticospinal excitability (MEP/Mmax) and corticomotor integrity (MEP latency) in the vastus lateralis (VL) and rectus femoris (RF) muscles during each NME. Results: MVC declined to a greater extent at exhaustion in the HF group compared to the other groups (P = .032) in part due to a larger decline in PT compared to CON (P = .041). EMG-RMS/Mmax in the VL (last commonly completed stage (NME3): P = .047; exhaustion: P = .006), and MEP/Mmax amplitude in the VL (NME3: P = .042; exhaustion: P = .029) and in the RF (NME3: P < .001; exhaustion: P = .007 at exhaustion) were consistently lower in HF compared to CON while MEP latency was consistently longer in HF in the VL (NME3: P = .010; exhaustion: P = .009) and RF (NME3: P = .038; exhaustion: P = .038) compared to CON. Conclusion: Cycling results in greater neuromuscular fatigue at exhaustion in PwMS who experience chronic fatigue than in healthy controls due to central and peripheral alterations.
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    Trafficking and regulation of neuronal voltage-gated calcium channels
    (Elsevier, 2007-07-12) Jarvis, Scott E.; Zamponi, Gerald W.
    The importance of voltage-gated calcium channels is underscored by the multitude of intracellular processes that depend on calcium, notably gene regulation and neurotransmission. Given their pivotal roles in calcium (and hence, cellular) homeostasis, voltage-gated calcium channels have been the subject of intense research, much of which has focused on channel regulation. While ongoing research continues to delineate the myriad of interactions that govern calcium channel regulation, an increasing amount of work has focused on the trafficking of voltage-gated calcium channels. This includes the mechanisms by which calcium channels are targeted to the plasma membrane, and, more specifically, to their appropriate loci within a given cell. In addition, we are beginning to gain some insights into the mechanisms by which calcium channels can be removed from the plasma membrane for recycling and/or degradation. Here we highlight recent advances in our understanding of these fundamentally important mechanisms.