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Exocytosis of Nonclassical Neurotransmitters
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Xiao Su, Vincent R. Mirabella, Kenneth G. Paradiso, Zhiping P. Pang
Brain function relies on the regulated release of chemical substances known as neurotransmitters at specialized junctions between neurons called synapses. Synaptic transmission is mainly mediated by classical neurotransmitters such as glutamate and γ-amino butyric acid (GABA), which normally transduce fast information flow in the brain. This process is further regulated by released neuromodulators including monoamines and neuropeptides. Dysfunctional neurotransmission is a major component of many neurological disorders and neuropsychiatric disorders, which include schizophrenia, depression, bipolar disorders, and eating disorders, as well as neurodevelopmental disorders such as autism spectrum disorders (ASDs). Since the discovery of synapses over 100 years ago, scientists have made major breakthroughs in determining the mechanisms and function of synaptic transmission. While it is impossible to fully comprehend all that we now know about synaptic transmission, we will review many of the fundamental discoveries and our current knowledge on neurotransmitter release. It is indisputable that understanding the mechanism and regulation of neurotransmitter release is a fundamental area of investigation in unraveling how the brain works.
Neurotherapeutic Potential of Tinospora cordifolia
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Anuradha Sharma, Anmol Bhandari, Payal Bajaj, Gurcharan Kaur
Neurodegeneration is an irreversible condition associated with significant changes in the neuronal network, structure, and function, resulting in impaired nerve function as well as gradual cognitive dysfunctions and decline such as memory and learning (Prasansuklab et al., 2017). Alzheimer’s and Parkinson’s diseases are major neurodegenerative pathologies in aging populations, which affects a large fraction of population worldwide (Ho et al., 2019). Next to Alzheimer’s disease, the various other types of neurodegenerative diseases affecting global population are Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, dementia with Lewy bodies etc., with sporadic or familial occurrence. There are multiple pathological mechanisms, including oxidative stress, inflammation, aberrant calcium homeostasis, metabolic stress and disrupted bioenergetics, abnormal protein dynamics, and neurotransmitter release, which have been reported to contribute to the onset and development of neurodegenerative diseases (Jellinger, 2010; Farzaei et al., 2018; Lyon et al., 2019).
Pharmacotherapy of Neurochemical Imbalances
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Rupali Patil, Aman Upaganlawar, Suvarna Ingale
Other molecule which is able to bind Ca2+ is the phosphatase calcineurin that is a serine/threonine phosphatase. Occupation of the calcium-binding site makes a structural change that exposes a Ca2+-CaM binding site. Once Ca2+-CaM binds to a subunit, it becomes active, dephosphorylation a number of intracellular targets. Exocytosis process of neurotransmitter release from synaptic vesicles is known to be mediated via Synaptotagmin present in all neurons (Claudia and Fabiola, 2014).
Homocysteine can aggravate depressive like behaviors in a middle cerebral artery occlusion/reperfusion rat model: a possible role for NMDARs-mediated synaptic alterations
Published in Nutritional Neuroscience, 2023
Mengying Wang, Xiaoshan Liang, Qiang Zhang, Suhui Luo, Huan Liu, Xuan Wang, Na Sai, Xumei Zhang
VGLUT1 is a specific presynaptic protein that uploads glutamate in the synaptic vesicle before its release, and thus is one of the synaptic plasticity markers linked to glutamate neurotransmission. Complexins and SNAP-25, as the key players of the synaptic-vesicle fusion machinery, participate in glutamate transmission [44, 45]. These synaptic vesicle-associated proteins, which are required for vesicle fusion and neurotransmitter release, have been identified as possible factors involved in the pathophysiology of psychiatric disorders including depression. At present, many studies have found the changes in synaptic protein expression in neurological diseases including cerebral ischemia, Alzheimer's disease and memory dysfunction. For instance, in an animal model of electroconvulsive therapy, the mRNA levels of 6 synaptic-vesicle proteins were significantly regulated in the hippocampus [46]. Similarly, Kamat et al. [43] found that several synaptic vesicle-associated proteins including synaptophysin and SNAP-25 decreased in HCY-injected mice brain and further impaired the function of memory. Here, VGLUT1, Complexins and SNAP-25 were significantly reduced in HCY-treated MCAO rats and depression-like behavior occurred. This suggests that abnormalities in synaptic function may lead to the progression of depression in HCY-treated MCAO rats.
Approaches for the discovery of drugs that target K Na 1.1 channels in KCNT1-associated epilepsy
Published in Expert Opinion on Drug Discovery, 2022
Barbara Miziak, Stanisław J Czuczwar
Molecular studies on CBD have revealed the presence of diverse mechanisms of action of the compound. To begin with, it is worth noting the action of the endocannabinoid system, which includes: cannabinoid type-1 receptors (CB1) (mainly in the central nervous system) and cannabinoid type-2 receptors (CB2), the endocannabinoids (ECs): anandamide (AEA) and 2-arachydonoylglycerol (2-AG), as well as the proteins that are responsible for the uptake, synthesis as well as degradation of endocannabinoids. CB1 and CB2 receptors are coupled to G proteins, which when activated results in increased influx of K+ ions and membrane hyperpolarization. This condition reduces the chances of pre-synaptic terminal neurotransmitter release. Hence, one may encounter the term ECs as ‘retrograde messengers’ [88,92].
Opioid MOP receptor agonists in late-stage development for the treatment of postoperative pain
Published in Expert Opinion on Pharmacotherapy, 2022
Qiu Qiu, Joshua CJ Chew, Michael G Irwin
All opioid receptors are inhibitory G-protein coupled receptors (GPCRs). Although the clinical effects can differ, the signaling mechanism of inhibitory GPCRs are the same. When an opioid agonist binds to the receptor, the receptor complex undergoes a conformational change. The α subunit exchanges its bound guanosine diphosphate (GDP) for guanosine triphosphate (GTP). Subsequently, the α-GTP and βγ subunit dissociate and proceed to interact with effector proteins such as adenylate cyclase and modulate ion channels. With inhibitory GPCRs, agonism causes the inhibition of adenylyl cyclase, leading to the reduction in formation of intracellular adenosine monophosphate (cAMP). The βγ subunit activates G protein-coupled inwardly rectifying potassium channels and inhibits voltage gated calcium channels. This results in hyperpolarisation and decreased neurotransmitter release. Agonism also leads to the recruitment of GPCR kinase which phosphorylates the GPCR. The phosphorylated GPCR subsequently binds β-arrestin, and this family of cytosolic proteins has been implicated in causing respiratory depression, tolerance and constipation. Phosporylated GPCRs can be recycled to the cell membrane or undergo lysosomal degradation [12–15] (Figure 1). Reduced available receptors via this mechanism is how the receptor is negatively regulated, and leads to decreased sensitivity and tolerance [16].