Journal of Neuroscience
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Comparison of N- and P/Q-Type Voltage-Gated Calcium Channel Current Inhibition Activation of N- and P/Q-type voltage-gated calcium channels triggers neurotransmitter release at central and peripheral synapses. These channels are targets for regulatory mechanisms, including inhibition by G-protein-linked receptors. Inhibition of P/Q-type channels has been less well studied than the extensively characterized inhibition of N-type channels, but it is thought that they are inhibited by similar mechanisms although possibly to a lesser extent than N-type channels. The aim of this study was to compare the inhibition of the two channel types. Calcium currents were recorded from adrenal chromaffin cells and isolated by the selective blockers ω-conotoxin GVIA (1 μm ) and ω-agatoxin IVA (400 nm ). The inhibition was elicited by ATP (100 μm ) or intracellular application of GTP-γ-S. It was classified as voltage-sensitive (relieved by a conditioning prepulse) or voltage-insensitive (present after a conditioning prepulse). The voltage-insensitive inhibition accounted for a 20% reduction of both currents, whereas the voltage-sensitive inhibition reduced the N-type current by 45% but the P/Q-type current by 18%. However, the voltage dependence of the inhibition, the time course of relief from inhibition during a conditioning prepulse, and the time course of reinhibition after such a prepulse showed few differences between the N- and P/Q-type channels. Assuming a simple bimolecular reaction, our data suggest that changes in the kinetics of the G-protein/channel interaction alone cannot explain the differences in the inhibition of the N- and P/Q-type calcium channels. The subtle differences in inhibition may facilitate the selective regulation of neurotransmitter release.
Journal of Neuroscience - Tập 17 Số 12 - Trang 4570-4579 - 1997
R-Type Ca<sup>2+</sup>Channels Are Coupled to the Rapid Component of Secretion in Mouse Adrenal Slice Chromaffin Cells Patch-clamp measurements of Ca2+ currents and membrane capacitance were performed on slices of mouse adrenal glands, using the perforated-patch configuration of the patch-clamp technique. These recording conditions are much closer to thein vivo situation than those used so far in most electrophysiological studies in adrenal chromaffin cells (isolated cells maintained in culture and whole-cell configuration). We observed profound discrepancies in the quantities of Ca2+ channel subtypes (P-, Q-, N-, and L-type Ca2+ channels) described for isolated mouse chromaffin cells maintained in culture. Differences with respect to previous studies may be attributable not only to culture conditions, but also to the patch-clamp configuration used. Our experiments revealed the presence of a Ca2+ channel subtype never before described in chromaffin cells, a toxin and dihydropyridine-resistant Ca2+ channel with fast inactivation kinetics, similar to the R-type Ca2+ channel described in neurons. This channel contributes 22% to the total Ca2+ current and controls 55% of the rapid secretory response evoked by short depolarizing pulses. Our results indicate that R-type Ca2+ channels are in close proximity with the exocytotic machinery to rapidly regulate the secretory process.
Journal of Neuroscience - Tập 20 Số 22 - Trang 8323-8330 - 2000
Epac Mediates a cAMP-to-PKC Signaling in Inflammatory Pain: An Isolectin B4(+) Neuron-Specific Mechanism The ϵ isoform of protein kinase C (PKCϵ) has emerged as a critical second messenger in sensitization toward mechanical stimulation in models of neuropathic (diabetes, alcoholism, and cancer therapy) as well as acute and chronic inflammatory pain. Signaling pathways leading to activation of PKCϵ remain unknown. Recent results indicate signaling from cAMP to PKC. A mechanism connecting cAMP and PKC, two ubiquitous, commonly considered separate pathways, remains elusive. We found that, in cultured DRG neurons, signaling from cAMP to PKCϵ is not mediated by PKA but by the recently identified cAMP-activated guanine exchange factor Epac. Epac, in turn, was upstream of phospholipase C (PLC) and PLD, both of which were necessary for translocation and activation of PKCϵ. This signaling pathway was specific to isolectin B4-positive [IB4(+)] nociceptors. Also, in a behavioral model, cAMP produced mechanical hyperalgesia (tenderness) through Epac, PLC/PLD, and PKCϵ. By delineating this signaling pathway, we provide a mechanism for cAMP-to-PKC signaling, give proof of principle that the mitogen-activated protein kinase pathway-activating protein Epac also stimulates PKC, describe the first physiological function unique for the IB4(+) subpopulation of sensory neurons, and find proof of principle that G-protein-coupled receptors can activate PKC not only through the G-proteins αq and βγ but also through αs .
Journal of Neuroscience - Tập 25 Số 26 - Trang 6119-6126 - 2005
A Persistent Activity-Dependent Facilitation in Chromaffin Cells Is Caused by Ca<sup>2+</sup>Activation of Protein Kinase C Activity-dependent facilitation was studied in bovine adrenal chromaffin cells. Stimulation with a train of depolarizations caused subsequent triggered exocytotic activity to be significantly enhanced. After the facilitating stimulus train, the readily releasable vesicle pool (RRP) size was estimated from capacitance jumps in response to paired depolarizations and found to be elevated for a period of at least 10 min. The time dependency of onset and degree of facilitation could be well fitted assuming protein kinase C (PKC)-dependent and independent Ca2+ -mediated processes. Both processes increase the recruitment of vesicles from the reserve pool to the RRP, resulting in an greater number of releasable vesicles. The data suggest that cell activity can act as a trigger to increase cytosolic Ca2+ to a level sufficient to cause an increase in the number of readily releasable secretory vesicles, with the more persistent component of the evoked facilitation being mediated through activity-dependent activation of PKC.
Journal of Neuroscience - Tập 19 Số 2 - Trang 589-598 - 1999
Coincident Elevation of cAMP and Calcium Influx by PACAP-27 Synergistically Regulates Vasoactive Intestinal Polypeptide Gene Transcription through a Novel PKA-Independent Signaling Pathway
Journal of Neuroscience - Tập 22 Số 13 - Trang 5310-5320 - 2002
NADPH Oxidase-Dependent Regulation of T-Type Ca<sup>2+</sup>Channels and Ryanodine Receptors Mediate the Augmented Exocytosis of Catecholamines from Intermittent Hypoxia-Treated Neonatal Rat Chromaffin Cells Nearly 90% of premature infants experience the stress of intermittent hypoxia (IH) as a consequence of recurrent apneas (periodic cessation of breathing). In neonates, catecholamine secretion from the adrenal medulla is critical for maintaining homeostasis under hypoxic stress. We recently reported that IH treatment enhanced hypoxia-evoked catecholamine secretion and [Ca2+ ]i responses in neonatal rat adrenal chromaffin cells and involves reactive oxygen species (ROS). The purpose of the present study was to identify the source(s) of ROS generation and examine the mechanisms underlying the enhanced catecholamine secretion by IH. Neonatal rats of either sex (postal day 0–5) were exposed to either IH or normoxia. IH treatment increased NADPH oxidase (NOX) activity, upregulated NOX2 and NOX4 transcription in adrenal medullae, and a NOX inhibitor prevented the effects of IH on hypoxia-evoked chromaffin cell secretion. IH upregulated Cav3.1 and Cav3.2 T-type Ca2+ channel mRNAs via NOX/ROS signaling and augmented T-type Ca2+ current in IH-treated chromaffin cells. Mibefradil, a blocker of T-type Ca2+ channels attenuated the effects of hypoxia on [Ca2+ ]i and catecholamine secretion in IH-treated cells. In Ca2+ -free medium, IH-treated cells exhibited higher basal [Ca2+ ]i levels and more pronounced [Ca2+ ]i responses to hypoxia compared with controls, and blockade of ryanodine receptors (RyRs) prevented these effects. RyR2 and RyR3 mRNAs were upregulated, RyR2 was S-glutathionylated in IH-treated adrenal medullae, and NOX/ROS inhibitors prevented these effects. These results demonstrate that neonatal IH treatment leads to NOX/ROS-dependent recruitment of T-type Ca2+ channels and RyRs, resulting in augmented [Ca2+ ]i mobilization and catecholamine secretion.
Journal of Neuroscience - Tập 30 Số 32 - Trang 10763-10772 - 2010
Spatial Attention, Motor Intention, and Bayesian Cue Predictability in the Human Brain Predictions about upcoming events influence how we perceive and respond to our environment. There is increasing evidence that predictions may be generated based upon previous observations following Bayesian principles, but little is known about the underlying cortical mechanisms and their specificity for different cognitive subsystems. The present study aimed at identifying common and distinct neural signatures of predictive processing in the spatial attentional and motor intentional system. Twenty-three female and male healthy human volunteers performed two probabilistic cueing tasks with either spatial or motor cues while lying in the fMRI scanner. In these tasks, the percentage of cue validity changed unpredictably over time. Trialwise estimates of cue predictability were derived from a Bayesian observer model of behavioral responses. These estimates were included as parametric regressors for analyzing the BOLD time series. Parametric effects of cue predictability in valid and invalid trials were considered to reflect belief updating by precision-weighted prediction errors. The brain areas exhibiting predictability-dependent effects dissociated between the spatial attention and motor intention task, with the right temporoparietal cortex being involved during spatial attention and the left angular gyrus and anterior cingulate cortex during motor intention. Connectivity analyses revealed that all three areas showed predictability-dependent coupling with the right hippocampus. These results suggest that precision-weighted prediction errors of stimulus locations and motor responses are encoded in distinct brain regions, but that crosstalk with the hippocampus may be necessary to integrate new trialwise outcomes in both cognitive systems. SIGNIFICANCE STATEMENT The brain is able to infer the environments' statistical structure and responds strongly to expectancy violations. In the spatial attentional domain, it has been shown that parts of the attentional networks are sensitive to the predictability of stimuli. It remains unknown, however, whether these effects are ubiquitous or if they are specific for different cognitive systems. The present study compared the influence of model-derived cue predictability on brain activity in the spatial attentional and motor intentional system. We identified areas with distinct predictability-dependent activation for spatial attention and motor intention, but also common connectivity changes of these regions with the hippocampus. These findings provide novel insights into the generality and specificity of predictive processing signatures in the human brain.
Journal of Neuroscience - Tập 37 Số 21 - Trang 5334-5344 - 2017
Pharmacological and ionic characterizations of the muscarinic receptors modulating [3H]acetylcholine release from rat cortical synaptosomes The muscarinic receptors that modulate acetylcholine release from rat cortical synaptosomes were characterized with respect to sensitivity to drugs that act selectively at M1 or M2 receptor subtypes, as well as to changes in ionic strength and membrane potential. The modulatory receptors appear to be of the M2 type, since they are activated by carbachol, acetylcholine, methacholine, oxotremorine, and bethanechol, but not by pilocarpine, and are blocked by atropine, scopolamine, and gallamine (at high concentrations), but not by pirenzepine or dicyclomine. The ED50S for carbachol, acetylcholine, and oxotremorine are less than 10 microM, suggesting that the high affinity state of the receptor is functional. High ionic strength induced by raising the NaCl concentration has no effect on agonist (oxotremorine) potency, but increases the efficacy of this compound, which disagrees with receptor- binding studies. On the other hand, depolarization with either KCl or with veratridine (20 microM) reduces agonist potencies by approximately an order of magnitude, suggesting a potential mechanism for receptor regulation.
Journal of Neuroscience - Tập 5 Số 5 - Trang 1202-1207 - 1985
Synaptic Islands Defined by the Territory of a Single Astrocyte
Journal of Neuroscience - Tập 27 Số 24 - Trang 6473-6477 - 2007
Trafficking and Fusion of Neuropeptide Y-Containing Dense-Core Granules in Astrocytes It is becoming clear that astrocytes are active participants in synaptic functioning and exhibit properties, such as the secretion of classical transmitters, previously thought to be exclusively neuronal. Whether these similarities extend to the release of neuropeptides, the other major class of transmitters, is less clear. Here we show that cortical astrocytes can synthesize both native and foreign neuropeptides and can secrete them in a stimulation-dependent manner. Reverse transcription-PCR and mass spectrometry indicate that cortical astrocytes contain neuropeptide Y (NPY), a widespread neuronal transmitter. Immunocytochemical studies reveal NPY-immunoreactive (IR) puncta that colocalize with markers of the regulated secretory pathway. These NPY-IR puncta are distinct from the synaptic-like vesicles that contain classical transmitters, and the two types of organelles are differentially distributed. After activation of metabotropic glutamate receptors and the release of calcium from intracellular stores, the NPY-IR puncta fuse with the cell membrane, and the peptide-containing dense cores are displayed. To determine whether peptide secretion subsequently occurred, exocytosis was monitored from astrocytes expressing NPY–red fluorescent protein (RFP). In live cells, after activation of glutamate receptors, the intensity of the NPY–RFP-labeled puncta declined in a step-like manner indicating a regulated release of the granular contents. Because NPY is a widespread and potent regulator of synaptic transmission, these results suggest that astrocytes could play a role in the peptidergic modulation of synaptic signaling in the CNS.
Journal of Neuroscience - Tập 28 Số 51 - Trang 13815-13827 - 2008
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