Regulation of cholinergic activity by the vesicular acetylcholine transporter

2013 ◽  
Vol 450 (2) ◽  
pp. 265-274 ◽  
Author(s):  
Vania F. Prado ◽  
Ashbeel Roy ◽  
Benjamin Kolisnyk ◽  
Robert Gros ◽  
Marco A. M. Prado
Keyword(s):  
Transmitter Release ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Cholinergic Neurons ◽  
Vesicular Acetylcholine Transporter ◽  
Cholinergic Activity ◽  
Neurotransmitter Transporter ◽  
Pathological Conditions ◽  
The Brain ◽  
Surprising Finding

Acetylcholine, the first chemical to be identified as a neurotransmitter, is packed in synaptic vesicles by the activity of VAChT (vesicular acetylcholine transporter). A decrease in VAChT expression has been reported in a number of diseases, and this has consequences for the amount of acetylcholine loaded in synaptic vesicles as well as for neurotransmitter release. Several genetically modified mice targeting the VAChT gene have been generated, providing novel models to understand how changes in VAChT affect transmitter release. A surprising finding is that most cholinergic neurons in the brain also can express a second type of vesicular neurotransmitter transporter that allows these neurons to secrete two distinct neurotransmitters. Thus a given neuron can use two neurotransmitters to regulate different physiological functions. In addition, recent data indicate that non-neuronal cells can also express the machinery used to synthesize and release acetylcholine. Some of these cells rely on VAChT to secrete acetylcholine with potential physiological consequences in the periphery. Hence novel functions for the oldest neurotransmitter known are emerging with the potential to provide new targets for the treatment of several pathological conditions.

scholarly journals Physical and functional interaction of the active zone proteins, CAST, RIM1, and Bassoon, in neurotransmitter release

2004 ◽  
Vol 164 (2) ◽  
pp. 301-311 ◽  
Author(s):  
Etsuko Takao-Rikitsu ◽  
Sumiko Mochida ◽  
Eiji Inoue ◽  
Maki Deguchi-Tawarada ◽  
Marie Inoue ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Active Zone ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Ternary Complex ◽  
Binding Region ◽  
Functional Interaction ◽  
Cervical Ganglion ◽  
Ganglion Neurons ◽  
The Brain

We have recently isolated a novel cytomatrix at the active zone (CAZ)–associated protein, CAST, and found it directly binds another CAZ protein RIM1 and indirectly binds Munc13-1 through RIM1; RIM1 and Munc13-1 directly bind to each other and are implicated in priming of synaptic vesicles. Here, we show that all the CAZ proteins thus far known form a large molecular complex in the brain, including CAST, RIM1, Munc13-1, Bassoon, and Piccolo. RIM1 and Bassoon directly bind to the COOH terminus and central region of CAST, respectively, forming a ternary complex. Piccolo, which is structurally related to Bassoon, also binds to the Bassoon-binding region of CAST. Moreover, the microinjected RIM1- or Bassoon-binding region of CAST impairs synaptic transmission in cultured superior cervical ganglion neurons. Furthermore, the CAST-binding domain of RIM1 or Bassoon also impairs synaptic transmission in the cultured neurons. These results indicate that CAST serves as a key component of the CAZ structure and is involved in neurotransmitter release by binding these CAZ proteins.

scholarly journals Distinct functional developments of surviving and eliminated presynaptic terminals

2021 ◽  
Vol 118 (11) ◽  
pp. e2022423118
Author(s):  
Mitsuharu Midorikawa ◽  
Mariko Miyata
Keyword(s):  
Transmitter Release ◽  
Synaptic Vesicles ◽  
Functional Differentiation ◽  
Dependent Manner ◽  
Presynaptic Terminals ◽  
Somatosensory Thalamus ◽  
Tightly Coupled ◽  
Refinement Process ◽  
The Brain ◽  
Developmental Maturation

For neuronal circuits in the brain to mature, necessary synapses must be maintained and redundant synapses eliminated through experience-dependent mechanisms. However, the functional differentiation of these synapse types during the refinement process remains elusive. Here, we addressed this issue by distinct labeling and direct recordings of presynaptic terminals fated for survival and for elimination in the somatosensory thalamus. At surviving terminals, the number of total releasable vesicles was first enlarged, and then calcium channels and fast-releasing synaptic vesicles were tightly coupled in an experience-dependent manner. By contrast, transmitter release mechanisms did not mature at terminals fated for elimination, irrespective of sensory experience. Nonetheless, terminals fated for survival and for elimination both exhibited developmental shortening of action potential waveforms that was experience independent. Thus, we dissected experience-dependent and -independent developmental maturation processes of surviving and eliminated presynaptic terminals during neuronal circuit refinement.

scholarly journals cAMP Modulates Intracellular Ca2+ Sensitivity of Fast-Releasing Synaptic Vesicles at the Calyx of Held Synapse

2010 ◽  
Vol 104 (6) ◽  
pp. 3250-3260 ◽  
Author(s):  
Lijun Yao ◽  
Takeshi Sakaba
Keyword(s):  
Transmitter Release ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Action Potentials ◽  
Calyx Of Held ◽  
Intracellular Ca ◽  
Underlying Mechanisms ◽  
Brain Stem Slices ◽  
Allosteric Model ◽  
Stem Slices

cAMP potentiates neurotransmitter release from the presynaptic terminal in many CNS synapses, but the underlying mechanisms remain unclear. Here we addressed this issue quantitatively by performing double patch-clamp recordings from the pre- and postsynaptic compartments of the calyx of Held synapse in rat brain stem slices in combination with Ca2+ uncaging. We found that elevation of cAMP increased intracellular Ca2+ sensitivity for transmitter release especially at lower Ca2+ concentrations. The change in Ca2+ sensitivity was limited to the fast-releasing synaptic vesicles, which could be released rapidly on action potentials. cAMP did not affect the slowly releasing vesicles. Fit of the data using a simplified allosteric model indicated that cAMP increased the fusion “willingness,” thereby facilitating transmitter release. We suggest that synaptic vesicles have to be positionally primed to the release sites close to the Ca2+ channel cluster for cAMP to modulate intracellular Ca2+ sensitivity of transmitter release.

Current Strategies and Novel Drug Approaches for Alzheimer Disease

2020 ◽  
Vol 19 (9) ◽  
pp. 676-690 ◽  
Author(s):  
Roma Ghai ◽  
Kandasamy Nagarajan ◽  
Meenakshi Arora ◽  
Parul Grover ◽  
Nazakat Ali ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholinergic Neurons ◽  
Amyloid Plaque ◽  
Neural Pathways ◽  
Current Trends ◽  
Personality Changes ◽  
Traditional Therapies ◽  
Novel Drug ◽  
The Brain

Alzheimer’s Disease (AD) is a chronic, devastating dysfunction of neurons in the brain leading to dementia. It mainly arises due to neuronal injury in the cerebral cortex and hippocampus area of the brain and is clinically manifested as a progressive mental failure, disordered cognitive functions, personality changes, reduced verbal fluency and impairment of speech. The pathology behind AD is the formation of intraneuronal fibrillary tangles, deposition of amyloid plaque and decline in choline acetyltransferase and loss of cholinergic neurons. Tragically, the disease cannot be cured, but its progression can be halted. Various cholinesterase inhibitors available in the market like Tacrine, Donepezil, Galantamine, Rivastigmine, etc. are being used to manage the symptoms of Alzheimer’s disease. The paper’s objective is to throw light not only on the cellular/genetic basis of the disease, but also on the current trends and various strategies of treatment including the use of phytopharmaceuticals and nutraceuticals. Enormous literature survey was conducted and published articles of PubMed, Scifinder, Google Scholar, Clinical Trials.org and Alzheimer Association reports were studied intensively to consolidate the information on the strategies available to combat Alzheimer’s disease. Currently, several strategies are being investigated for the treatment of Alzheimer’s disease. Immunotherapies targeting amyloid-beta plaques, tau protein and neural pathways are undergoing clinical trials. Moreover, antisense oligonucleotide methodologies are being approached as therapies for its management. Phytopharmaceuticals and nutraceuticals are also gaining attention in overcoming the symptoms related to AD. The present review article concludes that novel and traditional therapies simultaneously promise future hope for AD treatment.

Real-time measurement of transmitter release from single synaptic vesicles

Nature ◽  
1995 ◽  
Vol 377 (6544) ◽  
pp. 62-65 ◽  
Author(s):  
Dieter Bruns ◽  
Reinhard Jahn
Keyword(s):  
Real Time ◽  
Transmitter Release ◽  
Synaptic Vesicles ◽  
Time Measurement ◽  
Real Time Measurement

Distinct pools of synaptic vesicles in neurotransmitter release

Nature ◽  
1995 ◽  
Vol 375 (6531) ◽  
pp. 493-497 ◽  
Author(s):  
Vincent A. Pieribone ◽  
Oleg Shupliakov ◽  
Lennart Brodin ◽  
Sabine Hilfiker-Rothenfluh ◽  
Andrew J. Czernik ◽  
...  
Keyword(s):  
Neurotransmitter Release ◽  
Synaptic Vesicles

scholarly journals The role of CYP2D in rat brain in methamphetamine-induced striatal dopamine and serotonin release and behavioral sensitization

2021 ◽  
Author(s):  
Marlaina R. Stocco ◽  
Ahmed A. El-Sherbeni ◽  
Bin Zhao ◽  
Maria Novalen ◽  
Rachel F. Tyndale
Keyword(s):  
Neurotransmitter Release ◽  
Behavioral Sensitization ◽  
Serotonin Release ◽  
Striatal Dopamine ◽  
Irreversible Inhibitor ◽  
Drug Concentrations ◽  
Metabolite Concentrations ◽  
The Brain

Abstract Rationale Cytochrome P450 2D (CYP2D) enzymes metabolize many addictive drugs, including methamphetamine. Variable CYP2D metabolism in the brain may alter CNS drug/metabolite concentrations, consequently affecting addiction liability and neuropsychiatric outcomes; components of these can be modeled by behavioral sensitization in rats. Methods To investigate the role of CYP2D in the brain in methamphetamine-induced behavioral sensitization, rats were pretreated centrally with a CYP2D irreversible inhibitor (or vehicle) 20 h prior to each of 7 daily methamphetamine (0.5 mg/kg subcutaneous) injections. In vivo brain microdialysis was used to assess brain drug and metabolite concentrations, and neurotransmitter release. Results CYP2D inhibitor (versus vehicle) pretreatment enhanced methamphetamine-induced stereotypy response sensitization. CYP2D inhibitor pretreatment increased brain methamphetamine concentrations and decreased the brain p-hydroxylation metabolic ratio. With microdialysis conducted on days 1 and 7, CYP2D inhibitor pretreatment exacerbated stereotypy sensitization and enhanced dopamine and serotonin release in the dorsal striatum. Day 1 brain methamphetamine and amphetamine concentrations correlated with dopamine and serotonin release, which in turn correlated with the stereotypy response slope across sessions (i.e., day 1 through day 7), used as a measure of sensitization. Conclusions CYP2D-mediated methamphetamine metabolism in the brain is sufficient to alter behavioral sensitization, brain drug concentrations, and striatal dopamine and serotonin release. Moreover, day 1 methamphetamine-induced neurotransmitter release may be an important predictor of subsequent behavioral sensitization. This suggests the novel contribution of CYP2D in the brain to methamphetamine-induced behavioral sensitization and suggests that the wide variation in human brain CYP2D6 may contribute to differential methamphetamine responses and chronic effects.

scholarly journals Coenzyme Q10 and its effects in the treatment of neurodegenerative diseases

2009 ◽  
Vol 45 (4) ◽  
pp. 607-618 ◽  
Author(s):  
Graciela Cristina dos Santos ◽  
Lusânia Maria Greggi Antunes ◽  
Antonio Cardozo dos Santos ◽  
Maria de Lourdes Pires Bianchi
Keyword(s):  
Neurodegenerative Diseases ◽  
Health Risks ◽  
Coenzyme Q10 ◽  
Cellular Respiration ◽  
Irreversible Loss ◽  
Beneficial Effects ◽  
Pathological Conditions ◽  
Electron Transportation ◽  
The Brain ◽  
Lateral Sclerosis

According to clinical and pre-clinical studies, oxidative stress and its consequences may be the cause or, at least, a contributing factor, to a large number of neurodegenerative diseases. These diseases include common and debilitating disorders, characterized by progressive and irreversible loss of neurons in specific regions of the brain. The most common neurodegenerative diseases are Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Coenzyme Q10 (CoQ10) has been extensively studied since its discovery in 1957. It is a component of the electron transportation chain and participates in aerobic cellular respiration, generating energy in the form of adenosine triphosphate (ATP). The property of CoQ10 to act as an antioxidant or a pro-oxidant, suggests that it also plays an important role in the modulation of redox cellular status under physiological and pathological conditions, also performing a role in the ageing process. In several animal models of neurodegenerative diseases, CoQ10 has shown beneficial effects in reducing disease progression. However, further studies are needed to assess the outcome and effectiveness of CoQ10 before exposing patients to unnecessary health risks at significant costs.

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