China
Africa
Explore chapters and articles related to this topic
The Neuromuscular Junction
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
The structure of the ACh receptor has been determined using cryo-electron microscopic images of many receptors isolated from the muscle-derived, electric organ of the Torpedo ray. Figure 5.8a illustrates a longitudinal section through the channel. The ACh receptor is a large transmembrane protein having a molecular mass of about 290 kDa (kilodaltons, where the dalton is a unit of atomic mass equal to 1/12 of the atomic mass of 12C, or nearly 1.67 × 10–27 kg, the mass of a hydrogen atom). The receptor is about 7–8 nm in diameter and 16 nm in length. It protrudes about 7 nm into the external medium and about 5 nm into the cytoplasm. The receptor consists of five longitudinal strips arranged in a cylindrical configuration like the staves of a barrel (Figure 5.8b). The strips are subunits of the protein, identified clockwise, as α1, β1, δ, α1, and γ in fetal ACh receptors and ε in adult ACh receptors. Because it consists of five subunits, the receptor is a pentamer. Since the subunits are not all the same, the receptor is a heteromer, in contrast to a homomer having identical subunits. The receptor is therefore a pentameric heteromer.
Neurotransmitters in Characean Electrical Signaling
Published in Akula Ramakrishna, Victoria V. Roshchina, Neurotransmitters in Plants, 2018
Vilma Kisnieriene, Indre Lapeikaite, Vilmantas Pupkis
GABA is a major inhibitory neurotransmitter whose effect on Characean cells could be investigated using voltage clamp. GABA in CNS acts as a signal by regulating ion flow across cell membranes via two classes of receptors, the GABAA and GABAB (Bouché and Fromm 2004). Ionotropic GABAA receptors consist of multiple subunits that can assemble into a functional homomeric or heteromeric channel. GABA exerts its inhibitory effect in mature brain neurons by the activation of Cl− currents through GABAA receptor channels. This tends to hyperpolarize the membrane potential and inhibits excitability. In addition to acting on the ionotropic GABAA receptor, GABA is also an endogenous agonist of the GABAB receptor, which is a member of the large metabotropic G-protein coupled receptor superfamily (Lucas 2011).
Oxidation of Ion Channels in the Aging Process
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
A large number of diseases are associated with ion-channel dysfunction including epilepsy, congenital deafness, cardiac arrhythmia, and hypersecretion of insulin [10–16]. Typically, ion channels result from the assembly of several subunits. Such assemblies involve a circular arrangement of four identical or related pore-forming or alpha-subunits, packed around a water-filled pore and accessory or beta-subunits that modulate basic channel's attributes such as permeation, gating, trafficking, abundance on the plasma membrane, and pharmacology [17,18]. The genomes of Homo sapiens, Mus musculus (mouse), Gallus gallus (chicken), and Fugu rupribes (puffer fish) contain more than 200 ion channel genes each and invertebrate organisms including Caenorhabditis elegans (nematode), Drosophila melanogaster (fly), and Anopheles gambiae (mosquito) have similar numbers of ion-channel genes in their genomes [19]. Further heterogeneity arises from heteromeric ion channel complexes formed by the combination of different gene products.
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
The MOP receptor can undergo heteromerisation with another opioid receptor (e.g. MOP-DOP, MOP-KOP and DOP-KOP), or with a non-opioid receptor. Two receptors are then physically associated and exhibit distinct pharmacology from the constituent receptors. The heteromer can continue to interact with ligands of its constituent receptors and also bivalent ligands specific to the heteromer. The expression of heteromers is dynamic, for example, MOP-DOP heteromers are increased with chronic morphine administration. It has been demonstrated that occupancy of the binding site of one receptor (even at sub-signaling concentrations) increases the affinity and efficacy at the other binding site [26]. This draws parallels to allosteric modulation. Regarding the MOP-DOP heteromer, the addition of a DOP receptor agonist demonstrated synergistic antinociception. Counterintuitively, the addition of a DOP antagonist also demonstrated enhanced antinociception [27]. MDAN-21 is an example of a bivalent ligand that consists of a MOP and DOP receptor agonist linked by an amino-acid. In animal studies, it provides analgesia with limited tolerance [28]. It is theorized but not proven that MOP-NOP heteromers exist in vivo and contribute to the clinical effects of dual MOP and NOP receptor agonists, e.g. cebranopadol [29].
Ionotropic glutamate receptors in platelets: opposing effects and a unifying hypothesis
Published in Platelets, 2021
Maggie L. Kalev-Zylinska, Marie-Christine Morel-Kopp, Christopher M. Ward, James I. Hearn, Justin R. Hamilton, Anna Y. Bogdanova
Within their own types, subunits initially assemble in the endoplasmic reticulum as dimers (homomeric or heteromeric) and then organize into tetramers (dimers of dimers) to form mature receptors in the plasma membrane. The extracellular portion of the receptor contains the amino-terminal (ATD) and agonist-binding domains (ABD) that bind receptor modulators and ligands, respectively. The M1-M4 transmembrane segments form a pore of the ion channel (Figure 1B and C). The tip of the M2 loop contains the Q/R/N site subject to frequent editing at the mRNA level (Figure 1A and C; red marks) [10]. Editing controls Ca2+ permeability in AMPAR and KAR, and both Ca2+ permeability and Mg2+ block in NMDAR [11]. The intracellular C-terminal domain provides interaction with other proteins to help propagate the receptor signal downstream (Figure 1B) [2].
Targeting the receptor-based interactome of the dopamine D1 receptor: looking for heteromer-selective drugs
Published in Expert Opinion on Drug Discovery, 2019
Verònica Casadó-Anguera, Antoni Cortés, Vicent Casadó, Estefanía Moreno
A receptor oligomer has been defined as a macromolecular complex composed of at least two equals (homomers) or different (heteromers) functional receptor units (protomers) with biochemical and functional properties that are clearly differing from those of its individual components due to the allosteric modulations that occur within the oligomer [17]; this is named oligomer fingerprint [22]. In this line, one of the three consensus criteria to define GPCR heteromers established by the International Union of Basic and Clinical Pharmacology (IUPHAR) [22,23,45,46] is that heteromers have to exhibit specific properties, which must differ from those of their individual protomers, such as trafficking, ligand binding and signaling. The other two criteria are that heteromer components not only must co-localize in the same subcellular compartment but also physically interact in native tissues. In addition, heteromer disruption must lead to a loss of interaction and, as a consequence, a loss of its particular biochemical fingerprint. This pharmacological and/or functional fingerprint is a consequence of the allosteric interactions within the proteins of the heteromer.