scholarly journals Developmental Changes in Agonist-Induced Retrograde Signaling at Parallel Fiber–Purkinje Cell Synapses: Role of Calcium-Induced Calcium Release

2007 ◽  
Vol 98 (5) ◽  
pp. 2550-2565 ◽  
Author(s):  
Francis Crepel ◽  
Hervé Daniel
Keyword(s):  
Calcium Release ◽  
Cannabinoid Receptor ◽  
Parallel Fiber ◽  
Retrograde Signaling ◽  
Early Developmental Stage ◽  
Prolonged Release ◽  
Calcium Stores ◽  
Receptor Antagonists ◽  
Old Rats ◽  
Cerebellar Purkinje Cells

In cerebellar Purkinje cells (PCs), activation of postsynaptic mGluR1 receptors inhibits parallel fiber (PF) to PC synaptic transmission by retrograde signaling. However, results were conflicting with respect to whether endocannabinoids or glutamate (Glu) is the retrograde messenger involved. Experiments in cerebellar slices from 10- to 12-day-old rats and mice confirmed that suppression of PF-excitatory postsynaptic currents (EPSCs) by mGluR1 agonists was entirely blocked by cannabinoid receptor antagonists at this early developmental stage. In contrast, suppression of PF-EPSCs by mGluR1 agonists was only partly blocked by cannabinoid receptor antagonists in 18- to 22-day-old rats, and the remaining suppression was accompanied by an increase in paired-pulse facilitation. This endocannnabinoidindependent suppression of PF-EPSCs was potentiated by the Glu uptake inhibitor d-threo-β-benzyloxyaspartate (d-TBOA) and blocked by the desensitizing kainate (KA) receptors agonist SYM 2081, by nonsaturating concentrations of 6-cyano-7-nitroquinoxaline-2-3-dione (CNQX) [but not by GYKI 52466 hydrochloride (GYKI)] and by dialyzing PCs with guanosine 5′-[β-thio]diphosphate (GDP-βS). An endocannnabinoid-independent suppression of PF-EPSCs was also present in nearly mature wild-type mice but was absent in GluR6−/− mice. The endocannnabinoid-independent suppression of PF-EPSCs induced by mGluR1 agonists and the KA-dependent component of depolarization-induced suppression of excitation (DSE) were blocked by ryanodine acting at a presynaptic level. We conclude that retrograde release of Glu by PCs participates in mGluR1 agonist-induced suppression of PF-EPSCs at nearly mature PF-PC synapses and that Glu operates through activation of presynaptic KA receptors located on PFs and prolonged release of calcium from presynaptic internal calcium stores.

Developmental Changes in Retrograde Messengers Involved in Depolarization-Induced Suppression of Excitation at Parallel Fiber-Purkinje Cell Synapses in Rodents

2007 ◽  
Vol 97 (1) ◽  
pp. 824-836 ◽  
Author(s):  
Francis Crepel
Keyword(s):  
Purkinje Cell ◽  
Indirect Effects ◽  
Cannabinoid Receptor ◽  
Parallel Fiber ◽  
Developmental Changes ◽  
Wild Type ◽  
Cb1 Cannabinoid Receptor ◽  
Old Rats ◽  
Rats And Mice ◽  
Retrograde Messenger

At parallel fiber (PF) to Purkinje cell (PC) synapses, depolarization-induced suppression of excitation (DSE) and suppression of PF-excitatory postsynaptic currents (EPSCs) by activation of postsynaptic mGluR1 glutamate (Glu) receptors involve retrograde release of endocannabinoids. However, Levenes et al. suggested instead that Glu was the retrograde messenger in this latter case. Because the study by Levenes et al. was performed in nearly mature rats, whereas most others were performed in juvenile animals, DSE was re-investigated in juvenile versus nearly mature rats and mice. Indeed, DSE was preferred here to agonist-induced suppression of PF-EPSCs, to avoid possible indirect effects in this latter case. In 10- to 12-day-old rats, DSE of PF-EPSCs was entirely mediated through retrograde release of endocannabinoids. In 18- to 22-day-old-rats, DSE was partly resistant to CB1 cannabinoid receptor antagonists. The remaining component was potentiated by the Glu uptake inhibitor d-threo-beta-benzyloxyaspartate (d-TBOA) and blocked by the desensitizing kainate (KA) receptor agonist (2S,4R)-4-methylglutamic acid (SYM 2081). This SYM-2081-sensitive component of DSE was accompanied by a paired-pulse facilitation increase that was also potentiated by d-TBOA and blocked by SYM 2081. In nearly mature wild-type and GluR6 −/− mice, results fully confirmed the presence of an endocannabinoid-independent component of DSE that involves retrograde release of Glu and activation of presynaptic KA receptors including GluR6 receptor subunits. Therefore retrograde release of Glu by PCs participates to DSE at PF-PC synapses in nearly mature rodents but not in juvenile ones, and Glu probably operates through activation of presynaptic KA receptors that include GluR6 receptor subunits.

scholarly journals The Role of Protein Kinase A in the Ethanol-Induced Increase in Spontaneous GABA Release Onto Cerebellar Purkinje Neurons

2008 ◽  
Vol 100 (6) ◽  
pp. 3417-3428 ◽  
Author(s):  
M. Katherine Kelm ◽  
Hugh E. Criswell ◽  
George R. Breese
Keyword(s):  
Protein Kinase ◽  
Adenylate Cyclase ◽  
Protein Kinase A ◽  
Calcium Release ◽  
Cannabinoid Receptor ◽  
Gaba Release ◽  
Calcium Stores ◽  
Postsynaptic Neuron ◽  
Current Frequency ◽  
Kinase A

Ethanol increases miniature inhibitory postsynaptic current frequency and decreases the paired-pulse ratio, which suggests that ethanol increases both spontaneous and evoked GABA release, respectively. We have shown previously that ethanol increases GABA release at the rat interneuron–Purkinje cell synapse and that this ethanol effect involves calcium release from internal stores; however, further exploration of the mechanism responsible for ethanol-enhanced GABA release was needed. We found that a cannabinoid receptor 1 (CB1) agonist, WIN-55212, and a GABAB receptor agonist, baclofen, decreased baseline spontaneous GABA release and prevented ethanol from increasing spontaneous GABA release. The CB1 receptor and GABAB receptor are Gα i–linked G protein–coupled receptors with common downstream messengers that include adenylate cyclase and protein kinase A (PKA). Adenylate cyclase and PKA antagonists blocked ethanol from increasing spontaneous GABA release, whereas a PKA antagonist limited to the postsynaptic neuron did not block ethanol from increasing spontaneous GABA release. These results suggest that presynaptic PKA plays an essential role in ethanol-enhanced spontaneous GABA release. Similar to ethanol, we found that the mechanism of the cannabinoid-mediated decrease in spontaneous GABA release involves internal calcium stores and PKA. A PKA antagonist decreased baseline spontaneous GABA release. This effect was reduced after incubating the slice with a calcium chelator, BAPTA-AM, but was unaffected when BAPTA was limited to the postsynaptic neuron. This suggests that the PKA antagonist is acting through a presynaptic, calcium-dependent mechanism to decrease spontaneous GABA release. Overall, these results suggest that PKA activation is necessary for ethanol to increase spontaneous GABA release.

scholarly journals The Ryanodine Receptor: Arrhythmias and Muscle Disorders at High Resolution

2014 ◽  
Vol 70 (a1) ◽  
pp. C798-C798
Author(s):  
Filip Van Petegem
Keyword(s):  
Ryanodine Receptor ◽  
Calcium Release ◽  
Second Messengers ◽  
Mammalian Species ◽  
Prolonged Release ◽  
Calcium Stores ◽  
Closed State ◽  
Disease Mutations ◽  
Channel Opening ◽  
Domain Interactions

Calcium ions play crucial roles in our bodies, acting as second messengers in multiple signaling pathways. The resting calcium levels in the cytosol are very low, but can increase rapidly and transiently by influx from the extracellular space, or by release from intracellular stores. The Endoplasmic and Sarcoplasmic Reticulum (ER/SR) form major intracellular calcium stores. The `Ryanodine Receptor' (RyR) is a protein that dictates calcium release from the ER/SR. It forms a huge ion channel with a molecular weight exceeding 2 MegaDalton. RyRs are expressed in multiple cell types, but are particularly abundant in cardiac and skeletal muscle, where they are directly involved in excitation-contraction coupling. Three RyR isoforms exist in mammalian species (RyR1, RyR2, RyR3). Mutations in RyR1 and RyR2 have been linked to a number of devastating genetic disorders, including stress-induced cardiac arrhythmias (CPVT), malignant hyperthermia, and central core disease. In the past 5 years we have been solving crystal structures of several RyR domains. Cryo-electron microscopy structures have helped us to build pseudo-atomic models, allowing us to locate these domains in full-length RyRs. Over 80 disease mutations are scattered throughout the structures. The bulk of these affect domain-domain interactions. By comparing the RyR in the open and closed state, we find that some of these interactions are labile: they are disrupted during channel opening. Many disease mutations weaken these interactions, leading to facilitated channel opening, resulting in premature or prolonged release of calcium. In addition, many other disease mutations affect the same labile interactions allosterically. Stabilizing the closed-state domain-domain interactions may therefore be of therapeutic value.

scholarly journals Injection of inositol trisphosphorothioate into Limulus ventral photoreceptors causes oscillations of free cytosolic calcium.

1991 ◽  
Vol 97 (6) ◽  
pp. 1165-1186 ◽  
Author(s):  
R Payne ◽  
B V Potter
Keyword(s):  
Membrane Potential ◽  
Calcium Release ◽  
Feedback Inhibition ◽  
Initial Response ◽  
Periodic Variation ◽  
Cytosolic Calcium ◽  
Ion Concentration ◽  
Free Calcium ◽  
Calcium Stores ◽  
Calcium Ion Concentration

Limulus ventral photoreceptors contain calcium stores sensitive to release by D-myo-inositol 1,4,5 trisphosphate (InsP3) and a calcium-activated conductance that depolarizes the cell. Mechanisms that terminate the response to InsP3 were investigated using nonmetabolizable DL-myo-inositol 1,4,5 trisphosphorothioate (InsPS3). An injection of 1 mM InsPS3 into a photoreceptor's light-sensitive lobe caused an initial elevation of cytosolic free calcium ion concentration (Cai) and a depolarization lasting only 1-2 s. A period of densensitization followed, during which injections of InsPS3 were ineffective. As sensitivity recovered, oscillations of membrane potential began, continuing for many minutes with a frequency of 0.07-0.3 Hz. The activity of InsPS3 probably results from the D-stereoisomer, since L-InsP3 was much less effective than InsP3. Injections of 1 mM InsP3 caused an initial depolarization and a period of densensitization similar to that caused by 1 mM InsPS3, but no sustained oscillations of membrane potential. The initial response to InsPS3 or InsP3 may therefore be terminated by densensitization, rather than by metabolism. Metabolism of InsP3 may prevent oscillations of membrane potential after sensitivity has recovered. The InsPS3-induced oscillations of membrane potential accompanied oscillations of Cai and were abolished by injection of ethyleneglycol-bis (beta-aminoethyl ether)-N,N'-tetraacetic acid. Removal of extracellular calcium reduced the frequency of oscillation but not its amplitude. Under voltage clamp, oscillations of inward current were observed. These results indicate that periodic bursts of calcium release underly the oscillations of membrane potential. After each burst, the sensitivity of the cell to injected InsP3 was greatly reduced, recovering during the interburst interval. The oscillations may, therefore, result in part from a periodic variation in sensitivity to a constant concentration of InsPS3. Prior injection of calcium inhibited depolarization by InsPS3, suggesting that feedback inhibition of InsPS3-induced calcium release by elevated Cai may mediate desensitization between bursts and after injections of InsPS3.

scholarly journals Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice

2009 ◽  
Vol 156 (7) ◽  
pp. 1154-1166 ◽  
Author(s):  
Gernot Riedel ◽  
Paola Fadda ◽  
Susan McKillop-Smith ◽  
Roger G Pertwee ◽  
Bettina Platt ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Receptor Antagonists

N-methyl-D-aspartate receptors at parallel fiber synapses in the dorsal cochlear nucleus

1996 ◽  
Vol 76 (3) ◽  
pp. 1639-1656 ◽  
Author(s):  
P. B. Manis ◽  
S. C. Molitor
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Cochlear Nucleus ◽  
Voltage Dependence ◽  
Slow Component ◽  
Current Source ◽  
Dorsal Cochlear Nucleus ◽  
Parallel Fiber ◽  
Receptor Antagonists ◽  
Oscillatory Response

1. N-methyl-D-aspartate (NMDA) binding and NMDA-receptors immunolocalization experiments have revealed an enhanced expression of these receptors in the outer two layers of the dorsal cochlear nucleus (DCN). The distribution of the receptors is congruent with the distribution of synapses produced by the granule cell-parallel fiber system. To determine the functional distribution and contribution of NMDA receptors at parallel fiber synapses, synaptic responses to parallel fiber stimulation were studied in in vitro brain slice preparations of the guinea pig and rat dorsal cochlear nucleus. 2. The field potential response to parallel fiber stimulation in guinea pigs includes three postsynaptic components. The short latency components (the P3(2) and N2(2)) are blocked by general excitatory receptor antagonists, including the non-NMDA-receptor blockers 6,7-dinitroquinoxaline-2,3-dione (DNQX) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but are insensitive to NMDA-receptor antagonists. 3. A slower component (P4(2)) is revealed when the slices are washed with a low magnesium solution to eliminate the magnesium block of currents through NMDA receptors. This slow component is reduced by D- or DL-2-amino-5-phosphonovaleric acid (D-APV, DL-APV) and 3-[(+/-)-2-carboxypiperazine-4-yl] propyl-1-phosphonate, but is not blocked by DNQX or CNQX. Eliminating the voltage dependence of the NMDA receptors also results in a complex oscillatory response in some slices. This response exhibits the same pharmacological sensitivity as the slow potential. The pharmacologic sensitivity to NMDA-receptor antagonists suggest that the slow component (P4(2)) and the associated oscillatory response are mediated through activation of NMDA receptors. 4. Current source-density analysis of the parallel fiber-evoked field potentials was carried out to determine the relative spatial distributions of the fast and slow synaptic currents. Both synaptic components were associated with a superficial current sink and a deeper current source, localized within the superficial 250 microM of the nucleus. The slow (APV-sensitive) current was slightly shifted in depth relative to the fast (DNQX-sensitive) current in three of five slices with the maximum current sink and source occurring approximately 16 microns further from the surface of the DCN. These data suggest that either the NMDA receptors are not present at all of the synapses that generate the fast non-NMDA currents or that postsynaptic cells with different dendritic distributions have different densities of NMDA receptors. 5. The types of cells in layers 1 and 2 exhibiting NMDA-receptor-mediated synaptic potentials were investigated. Intracellular recordings with sharp electrodes in guinea pig slices showed that eliminating the voltage dependence of the NMDA receptors in low magnesium revealed a slow excitatory postsynaptic potential (EPSP) in both simple and complex spiking cells. The late phase of the EPSP could be reduced by APV in both cell types. These results could be explained by NMDA receptors on the postsynaptic cells or by NMDA receptors on excitatory interneurons. Attempts to demonstrate an appropriate voltage dependence of the parallel fiber synaptic response in normal magnesium medium under current clamp were confounded by the intrinsic voltage-dependent conductances of the cells. 6. To determine whether NMDA receptors were present on postsynaptic cells, the direct sensitivity of DCN cells to NMDA application was examined during intracellular recording. Both simple spiking and complex spiking cells responded to NMDA with depolarization. The response to NMDA persisted when non-NMDA receptors were blocked with CNQX or DNQX. However in all cells tested, the response to NMDA was blocked by APV. These experiments further support the postsynaptic localization of NMDA receptors on both simple and complex spiking cells. (ABSTRACT TRUNCATED)

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