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Neurotransmitters Receptors, Transporters, and Ion Channels


Neurotransmitters Receptors Overview

Neurotransmitters Receptors, Transporters, and Ion Channels

According to a rough estimate, there are about 100 billion neurons in the human nervous system, and each neuron has thousands of synaptic sites in contact with other cells, thus forming an extremely complex neural network in which a large amount of information is processed and integrated, and leads to biological effects. Neurotransmitters are essential media for the transmission and processing of synaptic sites and are therefore important research objects in neurobiology in recent years. In the 1960s, only acetylcholine and several types of amino acids and monoamines were identified as neurotransmitters. In the 1970s, due to the development of new technologies such as immunohistochemistry, some traditional sites located in the hypothalamus are unexpectedly found. Peptide hormones of the pituitary or gastrointestinal tract are also widely present in other nerve sites and have been shown to have transmitter properties in succession. At present, there are dozens of compounds that are neurotransmitters. In recent years, they have gradually shifted from the research of their synthesis, release, metabolism and other fields to explore the physiological regulation mechanism of transmitters from different levels. There are several transmitters of neurotransmitters in complex neural networks, and the understanding of their specific mechanisms can help in the diagnosis and treatment of related diseases

Neurotransmitters Receptors

Several neurotransmitter receptors have been studied using recombinant DNA technology in combination with DNA functional expression. According to available data, these receptors can be divided into two types, a receptor with seven transmembrane helices and a ligand-gated receptor. The first has at least eight members, such as K-substance receptors, and neurotensin. In addition, the rhodopsin opsin protein, although not a transmitter receptor, also has the function of transmitting information, and it also belongs to this type. The amino acid sequence of such receptors is very similar. The relationship between hydrophilicity and hydrophobicity in the amino acid sequence was analyzed and it was found that they all have seven hydrophobic regions. Each zone has 20 to 25 hydrophobic amino acids. They may be transmembrane helix structures that embed receptors into the cell membrane. In addition, they are connected in series by a hydrophilic amino acid sequence to form a group of seven transmembrane receptors. These receptors not only have a typical structure but also have a similar mechanism of action. These receptors are all associated with the G protein. The mRNA of the receptor and G coupled to different receptors are injected into Xenopus oocytes, which can assemble the receptor on the membrane of the oocyte. When the receptor is excited, it activates the G intrinsic on the oocyte membrane, increases the activity of the phospholipase through the G protein, and increases the second messenger IP3, which releases the intracellular Ca2+, thereby opening the chloride channel, and producing specific biological effects. The K-substance receptor is the first neuropeptide receptor to elucidate the primary structure and is also thought to achieve biological effects by opening the chlorine channel through the G protein. The coupling of the receptor to Gs or G affects the activity of adenylate cyclase, resulting in a change in the second messenger cAMP. The receptor is coupled to more than one G protein to activate multiple messenger systems. For example, Oar, a low concentration agonist inhibits adenylate cyclase by G and activates PLC by Gp at high concentrations. This can be seen in the functional expression of rodent atrium, Xenopus oocytes, and Chinese hamster egg cells (CHO). There are three members of the family of ligand-gated receptors, namely NACHR, GABAAR and glycine receptors. Such receptors have the dual role of receptors and ion channels. Unlike pre-receptors, they are composed of multiple subunits. These subunits form a ion channel. The neurotransmitter binds to the receptor, alters the conformation of the receptor protein, and opens the ion channel to achieve the biological effects of the receptor. Each subunit constituting the receptor has a hydrophobic region, which may form an α-helical structure and become a transmembrane segment.

Neurotransmitters Transporters

Transmitter transporters regulate the concentration and distribution of transmitters within the synapse. These proteins not only play an important role in determining synaptic activity but are also neuropharmaceuticals. Because transmitters are directly related to diseases such as mental disorders and drug addictions, they have been extensively studied in biochemistry and pharmacology for many years. Since the amount of transporter on mammalian cells is less than 0.2% of membrane protein and is easily inactivated during isolation and purification, it is difficult to obtain sufficient research. Further analysis of the structure of transporter revealed that the transporter has no signal peptide, and both the N-terminus and the C-terminus are intracellular, and have the least conserved, which may be related to the difference in transporter function. There are 12 transmembrane regions in the transporter, and each transmembrane region consists of 18-25 amino acid residues. Transporters have several glycosylation sites and kinase recognition sites. The biological activity of the transporter depends on the presence of Na+ and Cl-. Transmembrane regions 1 and 7 may be involved in transmitter transport. There are different receptors in the transmitter, and different subtypes exist in the transporter. The energy required for transporter protein uptake is electrochemical energy. The transporters described above all belong to the Na-dependent transporter superfamily. However, depending on the Na+ / K+ and Na+ /Cl-, the transport proteins in the nervous system can be divided into two families. Family I includes GLAST, GLUT and EAACL. Based on the size of the respective homology and the nature of the transmitter, the family l can be divided into three subfamilies, and subfamily I consists of GAT, TAUT, CHOT, BETT. Another family currently only has PROT (valine transporter) and GLYT (glycine transporter). There are many subtypes of the transmitter transporter, and the transport proteins of the same transmitter in nerve cells and glial cells often differ. Even for the same transporter, there may be different substrate binding sites and affinity states. It should also be noted that the transmitter transporter can also be found on the plasma membrane of postsynaptic neurons.

Neurotransmitters Ion Channels

When the presynaptic membrane is depolarized, extracellular calcium ions enter the nerve endings through the voltage-gated calcium channel of the presynaptic membrane, which is critical for the release of synaptic vesicle neurotransmitters. The calcium ions that enter the presynaptic membrane can reduce the release of neurotransmitters. When the stimulus is given, a sag is formed between the calcium ion channels. Observation of the synaptic cross-section confirmed that the depression is a vesicle that is exocytosis. Incubation of frog muscles with fluorescein-labeled toxins revealed that the place of acetylcholine receptor and ω-CTX-Texas in postsynaptic membrane. Studies find that the presynaptic membrane calcium channel and the complex is completely corresponding, indicating that the calcium ion channel of the presynaptic membrane is located directly opposite the postsynaptic membrane receptor. According to the principle that aequorin can bind to calcium ions and fluoresce, the aequorin can be injected into the giant axon of the squid, and the calcium concentration of the region can be directly observed when the nerve endings are excited. The release of neurotransmitters depends on the voltage-gated calcium channel opening and calcium influx in the presynaptic membrane, but the calcium channel pathway subtypes of the presynaptic membrane are different in different parts. For example, neurons contain many N-type calcium channels, an N-type calcium channel blocker ω-CTXGVIA blocks the release of transmitters at the frog neuromuscular junction, but ω-CTX GVIA and L-type calcium channel blockers 1, 4-dihydropyridine (DHP) did not block transmitter release at the neuromuscular junction of mammals. The tissue distribution of different subtypes of calcium channels and their mediated neurotransmitter release can be studied using specific calcium channel blockers, recombinant or purified calcium channel proteins. Immunochemical staining using specific antibodies with different subtypes of calcium channels revealed that L-type channels exist mainly in the soma and dendrites near the central nervous system, and confirmed that the channel participates in long-term potentiation (LTP) effects. The channels are mainly distributed in the dendrites and nerve endings of neurons; the P-type channels are mainly distributed in the Purkinje cell dendrites and axon terminals in specific regions of the central nervous system. Hormone secretion from neurosecretory neurons in the hypothalamus is a process of cell-mediated mediated by L-type calcium channels, but the release of central neurotransmitters cannot be blocked by L-type calcium channel blocker DHP, indicating the release of neurotransmitters is independent of the L-type calcium channel. The N-type calcium channel blocker ω-CTXGVIA can partially block the release of various neurotransmitters such as glutamate, acetylcholine, dopamine, and norepinephrine, but the maximum blocking effect is only 30%. In addition to N-type calcium channels, other subtypes of calcium channels are also involved in the release of central neurotransmitters, such as P-type calcium channels. The release of glutamate from synaptosomes in the rat striatum can be blocked by the P-type calcium channel blocker ω-AgaIVA, but the release of dopamine can be regulated by the P-type calcium channel blocker ω AgaIVA. Inhibition can also be blocked by the N-type calcium channel blocker ω-CTXGVIA, which, although synergistic, does not completely block the release of dopamine (DA). The above results suggest that in addition to the N-type and P-type calcium channels, there are other types of calcium channels involved in the release of DA. Further experiments have revealed that some neurotransmitter release that cannot be blocked by N-type and P-type calcium channel blockers, but they can be blocked by some non-specific calcium channel toxins such as ωCTXMVIIC and ω-GTXSIA, suggesting that Q-type or R-type calcium channels may also be involved in the release of neurotransmitters.

References:

  1. Sánchez F I, Loddenkemper T. Subunit composition of neurotransmitter receptors in the immature and in the epileptic brain. Biomed Research International. 2014, 2014(2014):301950.
  2. Engidawork E, Aradska J, Lubec G. Neurotransmitter receptor complexes: methods for bioanalysis, their potentials and limitations. Reviews in the Neurosciences. 2016, 27(2):111-133.
  3. Marchetti C. Interaction of metal ions with neurotransmitter receptors and potential role in neurodiseases. Biometals. 2014, 27(6):1097-1113.
  4. Borroni M V, et al. The lipid habitats of neurotransmitter receptors in brain. BBA – Biomembranes. 2016, 1858(11):2662-2670.
  5. Polo E, Kruss S. Nanosensors for neurotransmitters. Analytical & Bioanalytical Chemistry. 2016, 408(11):2727-2741.

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