Modulation of the Ryanodine Receptor and Intracellular Calcium

Zalk, Ran; Lehnart, Stephan E.; Marks, Andrew R.

doi:10.1146/annurev.biochem.76.053105.094237

Cited by 322 publications

(280 citation statements)

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“…One potential explanation could be that PKA promotes activation of RyRs and IP3Rs, as occurs in muscle (25,26). If this happened in the nerve terminal, then inhibiting PKA would reduce octopamine-induced Ca 2+ mobilization.…”

Section: Resultsmentioning

confidence: 99%

Synaptic neuropeptide release induced by octopamine without Ca ²⁺ entry into the nerve terminal

Shakiryanova

Zettel

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Synaptic release of neurotransmitters is evoked by activity-dependent Ca 2+ entry into the nerve terminal. However, here it is shown that robust synaptic neuropeptide release from Drosophila motoneurons is evoked in the absence of extracellular Ca 2+ by octopamine, the arthropod homolog to norepinephrine. Genetic and pharmacology experiments demonstrate that this surprising peptidergic transmission requires cAMP-dependent protein kinase, with only a minor contribution of exchange protein activated by cAMP (epac). Octopamine-evoked neuropeptide release also requires endoplasmic reticulum Ca 2+ mobilization by the ryanodine receptor and the inositol trisphosphate receptor. Hence, rather than relying exclusively on activity-dependent Ca 2+ entry into the nerve terminal, a behaviorally important neuromodulator uses synergistic cAMP-dependent protein kinase and endoplasmic reticulum Ca 2+ signaling to induce synaptic neuropeptide release.N euromodulators induce presynaptic signaling to regulate fast neurotransmission triggered by activity-induced Ca 2+ entry into the nerve terminal. Neuromodulators also influence the very low rate of spontaneous quantal release of classical transmitters. However, because spontaneous release is functionally relevant only in specialized cases (1), neuromodulators are not believed to typically induce physiologically significant release in the absence of extracellular Ca 2+ . Studies of endocrine cells suggest that release of peptides packaged in large dense-core vesicles (LDCVs) also requires Ca 2+ entry because of the rarity of spontaneous LDCV fusion and the inefficient permeation of peptides through the LDCV-fusion pore (2, 3). However, because it is difficult to measure peptide release at intact synapses, a much more limited dataset supports the conclusion that Ca 2+ influx into the nerve terminal is absolutely required for peptidergic transmission. Thus, it remains unclear how neuromodulators control synaptic neuropeptide release.With this background in mind, we set out to study regulation of neuropeptide release at the Drosophila neuromuscular junction (NMJ) by octopamine-induced cAMP signaling. Octopamine, the homolog of norepinephrine in Drosophila, controls many behaviors by activating central G protein-coupled receptors that induce adenylyl cyclase activation and intracellular Ca 2+ release (4, 5).

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Section: Resultsmentioning

confidence: 99%

Synaptic neuropeptide release induced by octopamine without Ca ²⁺ entry into the nerve terminal

Shakiryanova

Zettel

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…CRAC channels differ from similar channels in skeletal muscle where the dihydropyridine-sensitive PM channel is already in contact with the type 1 ryanodine receptor in the sarcoplasmic reticulum, allowing a fast Ca 2ϩ response in muscle (Zalk et al, 2007). Thus, the cap may serve as a repository of preformed channels that would allow more rapid T-cell responses when encountering additional antigen.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

Barr

Bernot

Srikanth

et al. 2008

MBoC

129

142

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The proteins STIM1 and Orai1 are the long sought components of the store-operated channels required in T-cell activation. However, little is known about the interaction of these proteins in T-cells after engagement of the T-cell receptor. We found that T-cell receptor engagement caused STIM1 and Orai1 to colocalize in puncta near the site of stimulation and accumulate in a dense structure on the opposite side of the T-cell. FRET measurements showed a close interaction between STIM1 and Orai1 both in the puncta and in the dense cap-like structure. The formation of cap-like structures did not entail rearrangement of the entire endoplasmic reticulum. Cap formation depended on TCR engagement and tyrosine phosphorylation, but not on channel activity or Ca 2؉ influx. These caps were very dynamic in T-cells activated by contact with superantigen pulsed B-cells and could move from the distal pole to an existing or a newly forming immunological synapse. One function of this cap may be to provide preassembled Ca 2؉ channel components to existing and newly forming immunological synapses. INTRODUCTIONT-cell activation in response to antigen induces and requires the elevation of intracellular Ca 2ϩ (Hogan et al., 2003;Quintana et al., 2005;Feske, 2007). T-cell receptor (TCR) engagement leads to activation of well-documented signal transduction pathways that cause a rapid release of Ca 2ϩ from the endoplasmic reticulum (ER; Samelson, 2002;Panyi et al., 2004;Gwack et al., 2007a). The depletion of Ca 2ϩ from this internal store then leads to the opening of ion channels in the plasma membrane (PM) allowing an influx of Ca 2ϩ from outside the cell. The store-operated channel responsible for Ca 2ϩ influx in T-cells is known as the Ca 2ϩ release-activated Ca 2ϩ (CRAC) channel, which has been studied by electrophysiological techniques for many years (Lewis, 2001;Prakriya and Lewis, 2003;Cahalan et al., 2007;Hewavitharana et al., 2007;Hogan and Rao, 2007;Putney, 2007a).Sustained elevation of cytosolic Ca 2ϩ is required for complete T-cell activation (Iezzi et al., 1998;Lewis, 2001;Hogan et al., 2003;Feske, 2007). High levels of intracellular Ca 2ϩ are necessary to maintain the interaction between a T-cell and antigen-presenting cell (APC) that leads to formation of the specialized contact surface known as the immunological synapse (IS). Increased Ca 2ϩ levels are also required for the activation of transcription factors. In particular, elevated Ca 2ϩ maintains prolonged nuclear accumulation of nuclear factor of activated T-cells (NFAT) by activating the phosphatase calcineurin that dephosphorylates NFAT, allowing it to translocate to the nucleus and activate genes such as IL2 (Hogan et al., 2003;Macian, 2005). Several hours of Ca 2ϩ influx are required to complete the T-cell activation program, which involves expression of a large number of activation-associated genes (Lewis, 2001;Macian et al., 2002;Hogan et al., 2003).Although sustained Ca 2ϩ influx in T-cells has been studied for decades, the proteins involved have only been ident...

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“…In the presence of 3 and 10 μM Ca 2+ , Mg 2+ produced biphasic responses with IC 50(1) values of 0.40±0.13mM and 0.64±0.09mM, respectively. The IC 50 (2) values for Mg 2+ at 3 and 10μM Ca 2+ were 5.71±0.31mM and 4.18±0.16mM, respectively. At 100μM Ca 2+ , the first phase of Mg 2+ inhibition was not detected and only an incomplete (~40% of maximum), monophasic inhibition (IC 50 =4.06±0.40mM) was observed.…”

Section: Mg 2+ Inhibitionmentioning

confidence: 90%

Allosterically coupled calcium and magnesium binding sites are unmasked by ryanodine receptor chimeras

Voss

Allen

Pessah

et al. 2008

Biochemical and Biophysical Research Communications

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We studied cation regulation of wild type ryanodine receptor type 1 ( WT RyR1), type 3 ( WT RyR3) and RyR3/RyR1 chimeras (Ch) expressed in 1B5 dyspedic myotubes. Using [ 3 H]ryanodine binding to sarcoplasmic reticulum (SR) membranes, Ca 2+ titrations with WT RyR3 and three chimeras show biphasic activation that is allosterically coupled to attenuated inhibition relative to WT RyR1. Chimeras show biphasic Mg 2+ inhibition profiles at 3 and 10μM Ca 2+ , no observable inhibition at 20μM Ca 2+ and monophasic inhibition at 100μM Ca 2+ . Ca 2+ imaging of intact myotubes expressing Ch-4 exhibit caffeine-induced Ca 2+ transients with inhibition kinetics that are significantly slower than those expressing WT RyR1 or WT RyR3. Four new aspects of RyR regulation are evident: 1) high affinity (H) activation and low affinity (L) inhibition sites are allosterically coupled, 2) Ca 2+ facilitates removal of the inherent Mg 2+ block, 3) WT RyR3 exhibits reduced cooperativity between H activation sites when compared to WT RyR1, and 4) uncoupling of these sites in Ch-4 results in decreased rates of inactivation of caffeine-induced Ca transients.Keywords ryanodine receptors; calcium-induced calcium release; channel regulation Three isoforms of wild type ryanodine receptors ( WT RyR1, 2 and 3) are expressed in specialized regions of endoplasmic/sarcoplasmic reticulum (ER/SR) in most mammalian cells where they function as Ca 2+ Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Materials and Methods Chimeric RyR1/RyR3 constructsSpecific primers were designed for PCR amplification of the selected fragments using WT RyR1 as a template. Amplified fragments from WT RyR1 encoding aa 1681-2217 (Ch-17), 1924-2446 (Ch-21) and 1681-3770 (Ch-4) were inserted, in frame, into the endogenous restriction site(s) of HSV-RyR3 plasmid as described previously [20]. All chimeric constructs were cloned into the HSV-1 amplicon vector and packaged using a helper virus-free packaging system [22]. Cell culture, infection and membrane preparation1B5 myoblasts were cultured and differentiated into myotubes as described previously [20] and [23]. Plates with differentiated myotubes were infected with virion containing wild type and RyR1/RyR3 chimeric cDNA for 2 h and membrane extracts were prepared 36 h after infection. Myotubes were homogenized and membrane fractions obtained by differential centrifugation as described previously [24].[ cold buffer, placed into 5 ml scintillation cocktail (ScintiVerse; Fisher Scientific) and radioactivity counted. Equations for binding analysisCurve fitting was ...

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Modulation of the Ryanodine Receptor and Intracellular Calcium

Cited by 322 publications

References 152 publications

Synaptic neuropeptide release induced by octopamine without Ca ²⁺ entry into the nerve terminal

Synaptic neuropeptide release induced by octopamine without Ca ²⁺ entry into the nerve terminal

Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

Allosterically coupled calcium and magnesium binding sites are unmasked by ryanodine receptor chimeras

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Modulation of the Ryanodine Receptor and Intracellular Calcium

Cited by 322 publications

References 152 publications

Synaptic neuropeptide release induced by octopamine without Ca 2+ entry into the nerve terminal

Synaptic neuropeptide release induced by octopamine without Ca 2+ entry into the nerve terminal

Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

Allosterically coupled calcium and magnesium binding sites are unmasked by ryanodine receptor chimeras

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Synaptic neuropeptide release induced by octopamine without Ca ²⁺ entry into the nerve terminal

Synaptic neuropeptide release induced by octopamine without Ca ²⁺ entry into the nerve terminal