scholarly journals Homeostatic Depression Shows Heightened Sensitivity to Synaptic Calcium

2021 ◽  
Vol 15 ◽  
Author(s):  
Catherine J. Yeates ◽  
C. Andrew Frank
Keyword(s):  
Neurotransmitter Release ◽  
Calcium Release ◽  
Glutamate Transporter ◽  
Homeostatic Plasticity ◽  
Loss Of Function ◽  
Pharmacological Agents ◽  
Inositol Trisphosphate Receptor ◽  
Genes Encoding ◽  
Trisphosphate Receptor ◽  
Signaling Process

Synapses and circuits rely on homeostatic forms of regulation in order to transmit meaningful information. The Drosophila melanogaster neuromuscular junction (NMJ) is a well-studied synapse that shows robust homeostatic control of function. Most prior studies of homeostatic plasticity at the NMJ have centered on presynaptic homeostatic potentiation (PHP). PHP happens when postsynaptic muscle neurotransmitter receptors are impaired, triggering retrograde signaling that causes an increase in presynaptic neurotransmitter release. As a result, normal levels of evoked excitation are maintained. The counterpart to PHP at the NMJ is presynaptic homeostatic depression (PHD). Overexpression of the Drosophila vesicular glutamate transporter (VGlut) causes an increase in the amplitude of spontaneous events. PHD happens when the synapse responds to the challenge by decreasing quantal content (QC) during evoked neurotransmission—again, resulting in normal levels of postsynaptic excitation. We hypothesized that there may exist a class of molecules that affects both PHP and PHD. Impairment of any such molecule could hurt a synapse’s ability to respond to any significant homeostatic challenge. We conducted an electrophysiology-based screen for blocks of PHD. We did not observe a block of PHD in the genetic conditions screened, but we found loss-of-function conditions that led to a substantial deficit in evoked amplitude when combined with VGlut overexpression. The conditions causing this phenotype included a double heterozygous loss-of-function condition for genes encoding the inositol trisphosphate receptor (IP3R —itpr) and ryanodine receptor (RyR). IP3Rs and RyRs gate calcium release from intracellular stores. Pharmacological agents targeting IP3R and RyR recapitulated the genetic losses of these factors, as did lowering calcium levels from other sources. Our data are consistent with the idea that the homeostatic signaling process underlying PHD is especially sensitive to levels of calcium at the presynapse.

scholarly journals A class of synaptic signaling molecules required for homeostatic potentiation also tunes homeostatic depression

2020 ◽  
Author(s):  
Catherine J. Yeates ◽  
C. Andrew Frank
Keyword(s):  
Neurotransmitter Release ◽  
Calcium Release ◽  
Glutamate Transporter ◽  
Homeostatic Plasticity ◽  
Loss Of Function ◽  
Pharmacological Agents ◽  
Inositol Trisphosphate Receptor ◽  
Genes Encoding ◽  
Trisphosphate Receptor ◽  
Compensatory Plasticity

Synapses and circuits rely on homeostatic forms of regulation in order to transmit meaningful information. The Drosophila melanogaster neuromuscular junction (NMJ) is a well-studied synapse that shows robust homeostatic control of function. Most prior studies of homeostatic plasticity at the NMJ have centered on presynaptic homeostatic potentiation (PHP). PHP happens when postsynaptic muscle neurotransmitter receptors are impaired, triggering retrograde signaling that causes an increase in presynaptic neurotransmitter release. As a result, normal levels of evoked excitation are maintained. The counterpart to PHP at the NMJ is presynaptic homeostatic depression (PHD). Overexpression of the Drosophila vesicular glutamate transporter (VGlut) causes an increase in the amplitude of spontaneous events. PHD happens when the synapse responds to the challenge by decreasing quantal content during evoked neurotransmission, again, resulting in normal levels of postsynaptic excitation. We hypothesized that there may exist a class of molecules that affects both PHP and PHD. Impairment of any such molecule could hurt the ability of a synapse to respond to any significant homeostatic challenge. We conducted an electrophysiology-based screen for blocks of PHD. While we did not observe a block of PHD in the genetic conditions screened, we instead found loss-of-function conditions that led to excess depression, i.e., a substantial deficit in evoked amplitude when combined with VGlut overexpression. The conditions causing this phenotype included a double heterozygous loss-of-function condition for genes encoding the inositol trisphosphate receptor (IP3R, itpr) and ryanodine receptor (RyR). IP3Rs and RyRs gate calcium release from intracellular stores. Pharmacological agents targeting IP3R and RyR recapitulated the genetic losses of these factors, as did lowering calcium levels from other sources. Our data are consistent with the idea that some factors required for homeostatic potentiation are also required for the synapse to achieve appropriate levels of homeostatic depression. Loss of such factors may disorient compensatory plasticity signals.

Angiotensin II Ca2+ signaling in rat afferent arterioles: stimulation of cyclic ADP ribose and IP3 pathways

2005 ◽  
Vol 288 (4) ◽  
pp. F785-F791 ◽  
Author(s):  
Susan K. Fellner ◽  
William J. Arendshorst
Keyword(s):  
Calcium Release ◽  
Rat Kidney ◽  
Ang Ii ◽  
High Concentration ◽  
Inositol Trisphosphate Receptor ◽  
Cyclic Adp Ribose ◽  
Specific Antagonist ◽  
Afferent Arterioles ◽  
Trisphosphate Receptor ◽  
Calcium Induced Calcium Release

ANG II induces a rise in cytosolic Ca2+ ([Ca2+]i) in vascular smooth muscle (VSM) cells via inositol trisphosphate receptor (IP3R) activation and release of Ca2+ from the sarcoplasmic reticulum (SR). The Ca2+ signal is augmented by calcium-induced calcium release (CICR) and by cyclic adeninediphosphate ribose (cADPR), which sensitizes the ryanodine-sensitive receptor (RyR) to Ca2+ to further amplify CICR. cADPR is synthesized from β-nicotinamide adenine dinucleotide (NAD+) by a membrane-bound bifunctional enzyme, ADPR cyclase. To investigate the possibility that ANG II activates the ADPR cyclase of afferent arterioles, we used inhibitors of the IP3R, RyR, and ADPR cyclase. Afferent arterioles were isolated from rat kidney with the magnetized microsphere and sieving technique and loaded with fura-2 to measure [Ca2+]i. In Ca2+-containing buffer, ANG II increased [Ca2+]i by 125 ± 10 nM. In the presence of the IP3R antagonists TMB-8 and 2-APB, the peak responses to ANG II were reduced by 74 and 81%, respectively. The specific antagonist of cADPR 8-Br ADPR and a high concentration of ryanodine (100 μM) inhibited the ANG II-induced increases in [Ca2+]i by 75 and 69%, respectively. Nicotinamide and Zn2+ are known inhibitors of the VSM ADPR cyclase. Nicotinamide diminished the [Ca2+]i response to ANG II by 66%. In calcium-free buffer, Zn2+ reduced the ANG II response by 68%. Simultaneous blockade of the IP3 and cADPR pathways diminished the [Ca2+]i response to ANG II by 83%. We conclude that ANG II initiates Ca2+ mobilization from the SR in afferent arterioles via the classic IP3R pathway and that ANG II may lead to activation of the ADPR cyclase to form cADPR, which, via its action on the RyR, substantially augments the Ca2+ response.

scholarly journals Extraocular muscle function is impaired in ryr3−/− mice

2019 ◽  
Vol 151 (7) ◽  
pp. 929-943 ◽  
Author(s):  
Jan Eckhardt ◽  
Christoph Bachmann ◽  
Marijana Sekulic-Jablanovic ◽  
Volker Enzmann ◽  
Ki Ho Park ◽  
...  
Keyword(s):  
Muscle Contraction ◽  
Ryanodine Receptor ◽  
Muscle Function ◽  
Extraocular Muscle ◽  
Calcium Release ◽  
Neuronal Excitability ◽  
Extraocular Muscles ◽  
Inositol Trisphosphate Receptor ◽  
Physiological Processes ◽  
Trisphosphate Receptor

Calcium is an ubiquitous second messenger mediating numerous physiological processes, including muscle contraction and neuronal excitability. Ca2+ is stored in the ER/SR and is released into the cytoplasm via the opening of intracellular inositol trisphosphate receptor and ryanodine receptor calcium channels. Whereas in skeletal muscle, isoform 1 of the RYR is the main channel mediating calcium release from the SR leading to muscle contraction, the function of ubiquitously expressed ryanodine receptor 3 (RYR3) is far from clear; it is not known whether RYR3 plays a role in excitation–contraction coupling. We recently reported that human extraocular muscles express high levels of RYR3, suggesting that such muscles may be useful to study the function of this isoform of the Ca2+ channel. In the present investigation, we characterize the visual function of ryr3−/− mice. We observe that ablation of RYR3 affects both mechanical properties and calcium homeostasis in extraocular muscles. These changes significantly impact vision. Our results reveal for the first time an important role for RYR3 in extraocular muscle function.

scholarly journals Elesclomol restores mitochondrial function in genetic models of copper deficiency

2018 ◽  
Vol 115 (32) ◽  
pp. 8161-8166 ◽  
Author(s):  
Shivatheja Soma ◽  
Andrew J. Latimer ◽  
Haarin Chun ◽  
Alison C. Vicary ◽  
Shrishiv A. Timbalia ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Copper Deficiency ◽  
Copper Metabolism ◽  
Mitochondrial Respiratory Chain ◽  
Yeast Cells ◽  
Loss Of Function ◽  
Zebrafish Model ◽  
Pharmacological Agents ◽  
Copper Supplementation ◽  
Genes Encoding

Copper is an essential cofactor of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Inherited loss-of-function mutations in several genes encoding proteins required for copper delivery to CcO result in diminished CcO activity and severe pathologic conditions in affected infants. Copper supplementation restores CcO function in patient cells with mutations in two of these genes, COA6 and SCO2, suggesting a potential therapeutic approach. However, direct copper supplementation has not been therapeutically effective in human patients, underscoring the need to identify highly efficient copper transporting pharmacological agents. By using a candidate-based approach, we identified an investigational anticancer drug, elesclomol (ES), that rescues respiratory defects of COA6-deficient yeast cells by increasing mitochondrial copper content and restoring CcO activity. ES also rescues respiratory defects in other yeast mutants of copper metabolism, suggesting a broader applicability. Low nanomolar concentrations of ES reinstate copper-containing subunits of CcO in a zebrafish model of copper deficiency and in a series of copper-deficient mammalian cells, including those derived from a patient with SCO2 mutations. These findings reveal that ES can restore intracellular copper homeostasis by mimicking the function of missing transporters and chaperones of copper, and may have potential in treating human disorders of copper metabolism.

Characterization of transepithelial potential oscillations in theDrosophilaMalpighian tubule

2001 ◽  
Vol 204 (17) ◽  
pp. 3075-3084 ◽  
Author(s):  
Edward M. Blumenthal
Keyword(s):  
Calcium Release ◽  
Chloride Concentration ◽  
Malpighian Tubule ◽  
Stellate Cells ◽  
Cell Types ◽  
Chloride Conductance ◽  
Potential Oscillations ◽  
Inositol Trisphosphate Receptor ◽  
Transepithelial Potential ◽  
Trisphosphate Receptor

SUMMARYThe Malpighian tubule of Drosophila melanogaster is a useful model system for studying the regulation of epithelial ion transport. In acutely isolated tubules, the transepithelial potential (TEP) undergoes large oscillations in amplitude with a period of approximately 30s. The TEP oscillations are diminished by reductions in the peritubular chloride concentration in a manner consistent with their being caused by fluctuations in chloride conductance. The oscillations are eliminated by pretreating tubules with the calcium chelator BAPTA-AM, although removal of peritubular calcium has no effect, suggesting that the oscillations are a result of either the release of calcium from intracellular stores or the entry of calcium from the tubule lumen. Transcripts encoding two calcium-release channels, the ryanodine receptor and the inositol trisphosphate receptor, are detectable in the tubule by reverse transcription–polymerase chain reaction. To identify the cell type responsible for the oscillations, tubules were treated with diuretic hormones known to alter calcium levels in each of the two cell types. Leucokinin-IV, which increases calcium levels in the stellate cells, suppressed the oscillations, whereas cardioacceleratory peptide 2b (CAP2b), which increases calcium levels in the principal cells, had no effect. These data are consistent with a model in which rhythmic changes in transepithelial chloride conductance, regulated by intracellular calcium levels in the stellate cells, cause the TEP oscillations.

Angiotensin II, reactive oxygen species, and Ca2+ signaling in afferent arterioles

2005 ◽  
Vol 289 (5) ◽  
pp. F1012-F1019 ◽  
Author(s):  
Susan K. Fellner ◽  
William J. Arendshorst
Keyword(s):  
Calcium Release ◽  
Rat Kidney ◽  
Specific Inhibitor ◽  
Oxygen Species ◽  
Ang Ii ◽  
Inositol Trisphosphate Receptor ◽  
Afferent Arterioles ◽  
Trisphosphate Receptor ◽  
Calcium Induced Calcium Release ◽  
Stimulation Of

In afferent arteriolar vascular smooth muscle cells, ANG II induces a rise in cytosolic Ca2+ ([Ca2+]i) via inositol trisphosphate receptor (IP3R) stimulation and by activation of the adenine diphosphate ribose (ADPR) cyclase to form cyclic ADPR, which sensitizes the ryanodine receptor (RyR) to Ca2+. We hypothesize that ANG II stimulation of NAD(P)H oxidases leads to the formation of superoxide anion (O2−·), which, in turn, activates ADPR cyclase. Afferent arterioles were isolated from rat kidney with the magnetized microsphere and sieving technique and loaded with fura-2 to measure [Ca2+]i. ANG II rapidly increased [Ca2+]i by 124 ± 12 nM. In the presence of apocynin, a specific inhibitor of NAD(P)H oxidase assembly, the [Ca2+]i response was reduced to 35 ± 5 nM ( P < 0.01). Tempol, a superoxide dismutase mimetic, did not alter the [Ca2+]i response to ANG II at a concentration of 10−4 M (99 ± 12 nM), but 10−3 M tempol reduced the response to 32 ± 3 nM ( P < 0.01). The addition of nicotinamide, an inhibitor of ADPR cyclase, to apocynin or tempol (10−3 M) resulted in no further inhibition. Measurement of superoxide production with the fluorescent probe tempo 9-AC showed that ANG II caused an increase of 48 ± 20 arbitrary units; apocynin or diphenyl iodonium (an inhibitor of flavoprotein oxidases) inhibited the response by 94%. Hydrogen peroxide (H2O2) was studied at physiological (10−7 M) and higher concentrations. In the presence of H2O2 (10−7 M), neither baseline [Ca2+]i nor the response to ANG II was altered (125 ± 15 nM), whereas H2O2 (10−6 and 10−5 M) inhibited the [Ca2+]i response to ANG II by 35 and 46%, respectively. We conclude that ANG II rapidly activates NAD(P)H oxidases of afferent arterioles, leading to the formation of O2−·, which then stimulates ADPR cyclase to form cADPR. cADPR, by sensitizing the RyR to Ca2+, augments the Ca2+ response (calcium-induced calcium release) initiated by activation of the IP3R.

Voltage-gated Ca2+ entry and ryanodine receptor Ca2+-induced Ca2+ release in preglomerular arterioles

2007 ◽  
Vol 292 (5) ◽  
pp. F1568-F1572 ◽  
Author(s):  
Susan K. Fellner ◽  
William J. Arendshorst
Keyword(s):  
Ryanodine Receptor ◽  
Calcium Release ◽  
Cyclopiazonic Acid ◽  
Inositol Trisphosphate Receptor ◽  
Voltage Gated ◽  
Closed Position ◽  
Afferent Arterioles ◽  
Voltage Gated Channels ◽  
Trisphosphate Receptor ◽  
Calcium Induced Calcium Release

We have previously shown that in afferent arterioles, angiotensin II (ANG II) involves activation of the inositol trisphosphate receptor (IP3R), activation of adenine diphosphoribose (ADPR) cyclase, and amplification of the initial IP3R-stimulated release of cytosolic Ca2+ ([Ca2+]i) from the sarcoplasmic reticulum (SR) (Fellner SK, Arendshorst WJ. Am J Physiol Renal Physiol 288: F785–F791, 2004). The response of the ryanodine receptor (RyR) to local increases in [Ca2+]i is defined as calcium-induced calcium release (CICR). To investigate whether Ca2+ entry via voltage-gated channels (VGCC) can stimulate CICR, we treated fura 2-loaded, freshly isolated afferent arterioles with KCl (40 mM; high KCl). In control arterioles, peak [Ca2+]i increased by 165 ± 10 nM. Locking the RyR in the closed position with ryanodine (100 μM) inhibited the [Ca2+]i response by 59% ( P < 0.01). 8-Br cADPR, a specific blocker of the ability of cyclic ADPR (cADPR) to sensitize the RyR to Ca2+, caused a 43% inhibition. We suggest that the lower inhibition by 8-Br cADPR ( P = 0.02, ryanodine vs. 8-Br cADPR) represents endogenously active ADPR cyclase. Depletion of SR Ca2+ stores by inhibiting the SR Ca2+-ATPase with cyclopiazonic acid or thapsigargin blocked the [Ca2+]i responses to KCl by 51% ( P not significant vs. ryanodine or 8-Br cADPR). These data suggest that about half of the increase in [Ca2+]i induced by high KCl is accomplished by activation of CICR through the ability of entered Ca2+ to expose the RyR to high local concentrations of Ca2+ and that endogenous cADPR contributes to the process.

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