Involvement of R-type Ca2+channels in neurotransmitter release from spinal dorsolateral funiculus terminals synapsing motoneurons

The strength of synaptic connections varies significantly and is a key determinant of communication within neural circuits. Mechanistic insight into presynaptic factors that establish and modulate neurotransmitter release properties is crucial to understanding synapse strength, circuit function, and neural plasticity. We previously identified Drosophila Piccolo-RIM-related Fife, which regulates neurotransmission and motor behavior through an unknown mechanism. Here, we demonstrate that Fife localizes and interacts with RIM at the active zone cytomatrix to promote neurotransmitter release. Loss of Fife results in the severe disruption of active zone cytomatrix architecture and molecular organization. Through electron tomographic and electrophysiological studies, we find a decrease in the accumulation of release-ready synaptic vesicles and their release probability caused by impaired coupling to Ca2+ channels. Finally, we find that Fife is essential for the homeostatic modulation of neurotransmission. We propose that Fife organizes active zones to create synaptic vesicle release sites within nanometer distance of Ca2+ channel clusters for reliable and modifiable neurotransmitter release.

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Fentanyl Decreases Ca2+Currents in a Population of Capsaicin-responsive Sensory Neurons

Anesthesiology ◽

10.1097/00000542-200301000-00034 ◽

2003 ◽

Vol 98 (1) ◽

pp. 223-231 ◽

Cited By ~ 8

Author(s):

Thomas S. McDowell

Keyword(s):

Neurotransmitter Release ◽

Dorsal Root ◽

Dorsal Root Ganglion Neurons ◽

Patch Clamp Technique ◽

Opioid Agonist ◽

Excitatory Neurotransmitter ◽

Nociceptive Neurons ◽

Whole Cell Patch Clamp ◽

Ganglion Neurons ◽

Ca2 Channels

Background Neuraxial opioids produce analgesia in part by decreasing excitatory neurotransmitter release from primary nociceptive neurons, an effect that may be due to inhibition of presynaptic voltage-activated Ca2+ channels. The purpose of this study was to determine whether opioids decrease Ca2+ currents (I Ca ) in primary nociceptive neurons, identified by their response to the algogenic agent capsaicin. Methods I was recorded from acutely isolated rat dorsal root ganglion neurons using the whole cell patch clamp technique before, during, and after application of the micro -opioid agonist fentanyl (0.01-1 micro m). Capsaicin was applied to each cell at the end of the experiment. Results Fentanyl reduced I Ca in a greater proportion of capsaicin-responsive cells (62 of 106, 58%) than capsaicin-unresponsive cells (2 of 15, 13%; P < 0.05). Among capsaicin-responsive cells, the decrease in I Ca was 38 +/- 3% (n = 36, 1 micro m) in fentanyl-sensitive cells just 7 +/- 1% (n = 15, 1 micro m; P < 0.05) in fentanyl-insensitive cells. Among capsaicin-responsive cells, I Ca inactivated more rapidly in fentanyl-sensitive cells (tau, 52 +/- 4 ms, n = 22) than in fentanyl-insensitive cells (93 +/- 14 ms, n = 24; P < 0.05). This was not due to differences in the types of Ca2+ channels expressed as the magnitudes of omega-conotoxin GVIA-sensitive (N-type), nifedipine-sensitive (L-type), and GVIA/nifedipine-resistant (primarily P-/Q-type) components of I Ca were similar. Conclusions The results show that opioid-sensitive Ca2+ channels are expressed by very few capsaicin-unresponsive neurons but by more than half of capsaicin-responsive neurons. The identity of the remaining capsaicin-responsive (and therefore presumed nociceptive) neurons that express opioid-insensitive Ca2+ channels is unknown but may represent a potential target of future non-opioid-based therapies for acute pain.

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α2-Adrenergic Receptor and Isoflurane Modulation of Presynaptic Ca2+ Influx and Exocytosis in Hippocampal Neurons

Anesthesiology ◽

10.1097/aln.0000000000001213 ◽

2016 ◽

Vol 125 (3) ◽

pp. 535-546 ◽

Cited By ~ 9

Author(s):

Masato Hara ◽

Zhen-Yu Zhou ◽

Hugh C. Hemmings

Keyword(s):

Action Potential ◽

Neurotransmitter Release ◽

Adrenergic Receptor ◽

Presynaptic Inhibition ◽

Hippocampal Neurons ◽

Quantitative Imaging ◽

Volatile Anesthetics ◽

Fluorescent Biosensors ◽

Selective Antagonist ◽

Ca2 Channels

Abstract Background Evidence indicates that the anesthetic-sparing effects of α2-adrenergic receptor (AR) agonists involve α2A-AR heteroreceptors on nonadrenergic neurons. Since volatile anesthetics inhibit neurotransmitter release by reducing synaptic vesicle (SV) exocytosis, the authors hypothesized that α2-AR agonists inhibit nonadrenergic SV exocytosis and thereby potentiate presynaptic inhibition of exocytosis by isoflurane. Methods Quantitative imaging of fluorescent biosensors of action potential–evoked SV exocytosis (synaptophysin-pHluorin) and Ca2+ influx (GCaMP6) were used to characterize presynaptic actions of the clinically used α2-AR agonists dexmedetomidine and clonidine, and their interaction with isoflurane, in cultured rat hippocampal neurons. Results Dexmedetomidine (0.1 μM, n = 10) or clonidine (0.5 μM, n = 8) inhibited action potential–evoked exocytosis (54 ± 5% and 59 ± 8% of control, respectively; P < 0.001). Effects on exocytosis were blocked by the subtype-nonselective α2-AR antagonist atipamezole or the α2A-AR–selective antagonist BRL 44408 but not by the α2C-AR–selective antagonist JP 1302. Dexmedetomidine inhibited exocytosis and presynaptic Ca2+ influx without affecting Ca2+ coupling to exocytosis, consistent with an effect upstream of Ca2+–exocytosis coupling. Exocytosis coupled to both N-type and P/Q-type Ca2+ channels was inhibited by dexmedetomidine or clonidine. Dexmedetomidine potentiated inhibition of exocytosis by 0.7 mM isoflurane (to 42 ± 5%, compared to 63 ± 8% for isoflurane alone; P < 0.05). Conclusions Hippocampal SV exocytosis is inhibited by α2A-AR activation in proportion to reduced Ca2+ entry. These effects are additive with those of isoflurane, consistent with a role for α2A-AR presynaptic heteroreceptor inhibition of nonadrenergic synaptic transmission in the anesthetic-sparing effects of α2A-AR agonists.

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Structure and function of neuronal Ca2+ channels and their role in neurotransmitter release

Cell Calcium ◽

10.1016/s0143-4160(98)90055-0 ◽

1998 ◽

Vol 24 (5-6) ◽

pp. 307-323 ◽

Cited By ~ 268

Author(s):

William A. Catterall

Keyword(s):

Neurotransmitter Release ◽

Structure And Function ◽

And Function ◽

Ca2 Channels

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T-Type Ca2+ Channels Mediate Neurotransmitter Release in Retinal Bipolar Cells

Neuron ◽

10.1016/s0896-6273(01)00454-8 ◽

2001 ◽

Vol 32 (1) ◽

pp. 89-98 ◽

Cited By ~ 86

Author(s):

Zhuo-Hua Pan ◽

Hui-Juan Hu ◽

Paul Perring ◽

Rodrigo Andrade

Keyword(s):

Neurotransmitter Release ◽

Bipolar Cells ◽

Retinal Bipolar Cells ◽

Ca2 Channels

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A dual role for Cav1.4 Ca2+ channels in the molecular and structural organization of the rod photoreceptor synapse

eLife ◽

10.7554/elife.62184 ◽

2020 ◽

Vol 9 ◽

Author(s):

J Wesley Maddox ◽

Kate L Randall ◽

Ravi P Yadav ◽

Brittany Williams ◽

Jussara Hagen ◽

...

Keyword(s):

Neurotransmitter Release ◽

Building Blocks ◽

Molecular Assembly ◽

Mutant Form ◽

Rod Photoreceptor ◽

Axon Terminals ◽

Fundamental Information ◽

Photoreceptor Synapse ◽

Ca2 Channels ◽

Do So

Synapses are fundamental information processing units that rely on voltage-gated Ca2+ (Cav) channels to trigger Ca2+-dependent neurotransmitter release. Cav channels also play Ca2+-independent roles in other biological contexts, but whether they do so in axon terminals is unknown. Here, we addressed this unknown with respect to the requirement for Cav1.4 L-type channels for the formation of rod photoreceptor synapses in the retina. Using a mouse strain expressing a non-conducting mutant form of Cav1.4, we report that the Cav1.4 protein, but not its Ca2+ conductance, is required for the molecular assembly of rod synapses; however, Cav1.4 Ca2+ signals are needed for the appropriate recruitment of postsynaptic partners. Our results support a model in which presynaptic Cav channels serve both as organizers of synaptic building blocks and as sources of Ca2+ ions in building the first synapse of the visual pathway and perhaps more broadly in the nervous system.

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Pharmaceutical intervention on Ca2+/cAMP signaling interaction: benefits for combating neurodegeneration and diseases related to aging

International Journal of Human Anatomy ◽

10.14302/issn.2577-2279.ijha-17-1587 ◽

2017 ◽

Vol 1 (1) ◽

pp. 21-26 ◽

Cited By ~ 2

Author(s):

Afonso Caricati-Neto ◽

Leandro Bueno Bergantin

Keyword(s):

Neurotransmitter Release ◽

Intracellular Signaling ◽

Sympathetic Nerves ◽

Camp Signaling ◽

Channel Blockers ◽

Pharmaceutical Intervention ◽

Low Concentrations ◽

Adrenal Chromaffin ◽

Unexpected Outcome ◽

Ca2 Channels

The pharmaceutical intervention on the interaction between intracellular signaling pathways mediated by Ca2+ and cAMP (Ca2+/cAMP signaling interaction) could bring important benefits for combating neurodegeneration and diseases related to aging. This discovery emerged from classical neurotransmission studies using rodent vas deferens as a model. From classical reports using this model, the concept of Ca2+-dependent processes involved in the neurotransmission (Ca2+ influx triggers muscle contraction and neurotransmitter release) is amply accepted. Thus, Ca2+ channel blockers (CCB) due to reduction of Ca2+ influx through L-type voltage-activated Ca2+ channels (VACC) should reduce neurotransmission. Nonetheless, using this model, some studies performed since 1975 reported that reduction of Ca2+ influx by low concentrations of CCB (verapamil, diltiazem or nifedipine) produced a paradoxical increase of the contractions mediated by sympathetic nerves, a phenomenon known as âcalcium paradoxâ. Recent studies using adrenal chromaffin cells have also demonstrated that CCB caused a paradoxical increase of the catecholamine release. Because these compounds are blocking the L-type VACC, an augmented nerve-mediated response due to increased neurotransmitter release was an unexpected outcome. In 2013, we revealed that the Ca2+/cAMP signaling interaction could properly explain the so-called âcalcium paradoxâ. The original paper published by us in Cell Calcium (2013) has appeared four times in ScienceDirect TOP 25 Hottest Articles lists. In conclusion, these findings may significantly impact on neurodegenerative diseases, thus may stimulate the development of new pharmacological strategies to combat the diseases related to aging.

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Presynaptic Calcium Channels

International Journal of Molecular Sciences ◽

10.3390/ijms20092217 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2217 ◽

Cited By ~ 6

Author(s):

Sumiko Mochida

Keyword(s):

Neurotransmitter Release ◽

Synaptic Vesicles ◽

Neuronal Firing ◽

Regulatory Proteins ◽

Channel Modulation ◽

Signaling Complex ◽

Presynaptic Plasticity ◽

Presynaptic Calcium ◽

Ca2 Channels ◽

Α1 Subunit

Presynaptic Ca2+ entry occurs through voltage-gated Ca2+ (CaV) channels which are activated by membrane depolarization. Depolarization accompanies neuronal firing and elevation of Ca2+ triggers neurotransmitter release from synaptic vesicles. For synchronization of efficient neurotransmitter release, synaptic vesicles are targeted by presynaptic Ca2+ channels forming a large signaling complex in the active zone. The presynaptic CaV2 channel gene family (comprising CaV2.1, CaV2.2, and CaV2.3 isoforms) encode the pore-forming α1 subunit. The cytoplasmic regions are responsible for channel modulation by interacting with regulatory proteins. This article overviews modulation of the activity of CaV2.1 and CaV2.2 channels in the control of synaptic strength and presynaptic plasticity.

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