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Homeostasis of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
The span of presynaptic membrane that contains the primed vesicles and the dense collection of SNARE proteins is referred to as the active zone. Voltage-gated calcium channels are highly concentrated around the active zones and open in response to membrane depolarization at the synapse. The influx of calcium is sensed by synaptotagmin 1, which in turn dislodges the complexin protein and allows the vesicle to fuse with the presynaptic membrane and release the neurotransmitter. It has also been shown that the voltage-gated calcium channels directly interact with the t-SNAREs syntaxin 1A and SNAP-25, as well as with synaptotagmin 1. During exocytosis, v-SNAREs (e, g., synaptobrevin) and t-SNAREs (e.g., syntaxin and SNAP-25) assemble into a core trans-SNARE complex. This complex plays multiple roles during the various stages of exocytosis, including priming, fusion, pore formation, and expansion, eventually resulting in the release of the vesicle content.
Physiology, Biochemistry, and Pathology of Neuromuscular Transmission
Published in Marc H. De Baets, Hans J.G.H. Oosterhuis, Myasthenia Gravis, 2019
Ca2+ channels open and close as a function of both membrane potential and time. Upon arrival of the nerve action potential they open for a brief period of time allowing the inflow of enough Ca2+ ions needed for the catalysis of transmitter release. These channels are present at the active zones of transmitter release and are the same molecules which can be recognized as intramembrane particles at freeze fracture micrographs at the preterminal parts of the neuromuscular junction.71,72 Active zones are defined as sites for transmitter release; they are most conspicuous at the neuromuscular junction of the frog, where each active zone is characterized presynaptically by two parallel rows of vesicles and postsynaptically by a secondary fold, and AChRs situated at the interfold tops (see Figure 1). At least three distinct Ca2+ channels can be distinguished on the basis of their electrophysiological properties and their sensitivity to neurotoxins: the T, L, and N channels.73 It is uncertain whether the Ca2+ channels in motor nerve terminals belong to the L or N channel type or to a different, as yet unclassified, channel.
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
Vesicular exocytosis of dopamine also relies on the SNARE complex to mediate membrane fusion which consists of syntaxin, SNAP25, and synaptobrevin. Dopamine release is shown to be repressed partially by botulinum toxin A and B which are proteases for SNAP25 and synaptobrevin-2 respectively while another synaptobrevin-2 protease, tetanus toxin, has no effect on dopamine release (Bergquist et al., 2002; Fortin et al., 2006). This indirect evidence suggests that SNARE proteins play a role in regulating dopamine release. Nevertheless, future studies need to identify the relevant SNARE proteins. For fast synaptic transmission, the presynaptic active zone proteins dock and prime synaptic vesicles, recruit voltage-gated Ca2+ channels, align fusion locations with postsynaptic receptors, and mediate short- and long-term presynaptic plasticity (Südhof, 2012). However, the nature of volume transmission does not require precise localization and timing of secretion. This raises the question of how much the active zone machinery contributes to the release of dopamine. One recent study has shown that ~30% of dopamine varicosities in striatal dopamine neurons contain the presynaptic active zone consisting of bassoon, RIM, and ELKS (Liu et al., 2018). Knockout of RIM disrupted the presynaptic active zone scaffolding and impaired dopamine release while knockout of ELKS has no effect on dopamine release (Liu et al., 2018). The dopamine release was fast with a very high initial release probability with the assistance of protein scaffolds for coupling Ca2+ influx to vesicle fusion. In summary, the regulation of sparse specialized active zone-like release sites supports precise spatial and temporal secretion of dopamine (Liu et al., 2018).
Advances in molecular therapies for targeting pathophysiology in spinal cord injury
Published in Expert Opinion on Therapeutic Targets, 2023
Ha Neui Kim, Madeline R. McCrea, Shuxin Li
When mice with transection SCI were housed in an enriched environment, treatment with CSP-TTK21, a CBP/p300 activator, between 12 and 22 weeks after SCI stimulated motor and sensory axon growth, sprouting, and synaptic plasticity, but did not promote sensorimotor recovery [111]. A recent genomics study indicated that REST might be an upstream suppressor of a pro-regenerative gene program associated with CNS axon regeneration [112]. Upregulating Inpp5k, an enzyme to remove the phosphate on position 5 of inositol rings, could stimulate CST axon regrowth after pyramidotomy, stroke, and acute and chronic contusion injuries [113]. A genetic study showed that some synaptic vesicle priming proteins in the presynaptic active zone, including RIMs and Munc13s, suppressed the axon growth of adult neurons by activating voltage-gated Ca channels [114]. Systemic treatment with Baclofen, a GABA receptor agonist, could reduce voltage-dependent Ca influx in sensory neurons and promote their regeneration after SCI. PARP1 was upregulated by several growth inhibitors or CNS injury and its deletion or inhibition has been shown to facilitate axon regeneration of CNS neurons [115,116]. However, a recent study showed that PARP deletion or inhibition by systemic veliparib failed to induce axon regrowth and functional recovery in mice with either SCI or ONC [117].
Molecular docking studies, anti-Alzheimer’s disease, antidiabetic, and anti-acute myeloid leukemia potentials of narcissoside
Published in Archives of Physiology and Biochemistry, 2023
Tingting Liu, Lixia Cao, Tingting Zhang, Huan Fu
Firstly, it was used from Gaussian software program (Frisch et al.2009) to obtain optimised structures of molecules, which created files with *.sdf extension using these structures. Using these files, all calculations were made with Maestro Molecular modelling platform (version 12.2) by Schrödinger, LLC (2019a). Maestro Molecular modelling platform (version 12.2) by Schrödinger comes together from many modules. In the first module used, the protein preparation module (Friesner et al.2006, Schrödinger 2019b) was used for the preparation of proteins. There are many small proteins in the enzymes studied. The crystal structures of these proteins have been downloaded from the protein data bank site. These enzymes were initially minimised and the water molecules in the structure were removed. In the next step, the active sites of the enzymes were determined, in which the proteins in this active zone were given freedom of movement. Therefore, these proteins were enabled to interact with molecules more easily. In the next step, the molecule was prepared for calculations, the LigPrep module (Sastry et al.2013, Schrödinger 2019c) was used for this process.
Surround inhibition in patients with juvenile myoclonic epilepsy
Published in Neurological Research, 2021
Bengi Gul Turk, Naz Yeni, Aysegul Gunduz, Ceren Alis, Meral Kiziltan
Sensory gating at the level of midbrain was previously analyzed using midlatency auditory-evoked potentials [29] or prepulse inhibition of blink reflex [30] in focal epilepsies, in which there was a deficit. As far as we know, sensory gating or SI of SEPs was not studied in JME. Transcranial magnetic stimulation studies showed short intracortical inhibition, which is a GABAergic intracortical response, is reduced in JME [31]. After sleep deprivation, a reduction in GABAergic inhibitions deepens [31]. Cortical integration of sensory information is known to alter by the state of wakefulness or sleep [28]. For example, in the waking state, the extent of intracortical activity around the active zone is more widespread than during deep sleep [28]. In JME, we have previously shown that ascending control of the cortex by thalamus was preserved. However, the findings in this study suggest that the horizontal spread of the activity in the somatosensory cortex is impaired in JME, which may be attributed to the defective intracortical defective GABAergic transmission or cholinergic transmission since acetylcholine through muscarinic receptors is a strong activator of GABAergic neurons [32]. Long-term potentiation was analyzed using PAS protocol in JME that revealed no potentiation in patients in contrast to healthy subjects [33]. However, the authors analyzed its effect upon motor-evoked potentials, meaning on motor cortex. Thus, there is no direct evidence of abnormal long-term potentiation in somatosensory cortex in JME. However, abnormal SI may be an indirect evidence and this issue may warrant further analysis.