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Stimulus-Secretion Coupling: Receptors
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
Higgins and Berg (1988c) showed that a cAMP-dependent process enhances the function of adrenal chromaffin nicotinic acetylcholine receptors as a population in the plasma membrane. This was demonstrated by showing that cAMP analogues caused specific increases both in the level of nicotine-induced catecholamine release from the cells and in the level of the nicotine-induced conductance change occurring in the cells. The responsiveness of the receptors to regulation appears to depend on the length of time the receptors have been on the cell surface. Receptors that have been newly inserted into the plasma membrane generate a greater nicotinic response than do older receptors; and unlike older receptors, their response to agonists is not enhanced after treatment of the cells with cAMP analogues. Their findings indicated that nicotinic acetylcholine receptors or associated components undergo a maturation in the plasma membrane that alters their function and their regulation by second-messenger systems.
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
Non-NMDA receptors are also targets for several sulfated GABA-inhibiting ste-roids.11,20 PS and other sulfated steroids depress non-NMDA receptor-mediated responses at high micromolar concentrations. Compared with the NMDA receptor, less is known about the structural requirements of the ligand or receptor for these effects, although apparently both AMPA and kainate receptor function are depressed by PS.23Nicotinic Acetylcholine Receptors
Functional characterisation of the GABAA receptors
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
The early photolabelling and peptide mapping experiments with the agonist muscimol suggested that it labelled the 13 subunits (Casalotti et al, 1986; Deng et al, 1986; Bureau and Olsen, 1988), although later studies suggested additional labelling of the a subunits (Smith and Olsen, 1994). Subsequent mutagenesis experiments have identified a number of residues in the N-terminal domain of both the α and β subunits that are important in channel activation. In the first of these experiments a single amino acid F64 of the al subunit when mutated to leucine (α1-F64L) produced a 200- fold decrease in the affinity of GABA and similar reductions in the affinity of the competitive antagonists bicuculline and SR 95531 (Sigel et al, 1992). More recent studies have demonstrated the importance of two neighbouring residues, R66 and S68, within this α subunit recognition loop, the evidence from which suggests that it is constrained within a β-strand (Boileau and Czajkowski, 1999). Four additional amino acids have been identified in the β subunits which appear to be important in agonist recognition: Y157, T160, T202 and Y205 (Amin and Weiss, 1993). By analogy with similar studies carried out on the nicotinic acetylcholine receptor, these amino acids have been allocated to loops B (Y157 and T160) and C (T202 and Y205) on the 13 subunits and loop D on the a subunit (F64). In each case it has been shown that mutagenesis in the homologous positions of the other subunits does not compromise channel activation, compatible with the notion that it is the αβ interface only which is important in the formation of the very low affinity (activating) site.
The α9α10 nicotinic acetylcholine receptor: a compelling drug target for hearing loss?
Published in Expert Opinion on Therapeutic Targets, 2022
Nicotinic acetylcholine receptors are a subfamily of the pentameric ligand-gated ion channels involved in many physiological and pathological processes [47]. Each receptor subtype is composed of different subunits, encoded by paralogous genes. They show a similar fivefold symmetrical arrangement of subunits around a central pore and are composed of extracellular and transmembrane (TM) domains (Figure 1). The extracellular domain contains the orthosteric ligand-binding sites and folds into a highly conserved immunoglobulin-like β-sandwich. The TM domain consists of four α-helices, with TM2 lining the channel pore, surrounded by a ring made of TM1 and TM3 α-helices [47,48]. According to their main tissue of expression, in vertebrates, they are divided into three subgroups: neuronal, muscle, and hair cell nAChRs [49]. Thus, neuronal nAChRs are formed by as yet not fully characterized combinatorial arrangements of α2-α7 (α8 in non-mammals) and β2-4 subunits [50–52]. In addition, receptors formed by the same subunits, but with alternate stoichiometry [53–58], further extend the complexity of neuronal nAChRs. On the other hand, muscle receptors are formed by α12 β1γ, and δ, or ε subunits [59,60]. Finally, and in contrast to neuronal receptors, the nAChR subunits expressed in cochlear hair cells have a very strict co-assembly pattern, encompassing only α9 and α10 subunits [61–63].
Sleep Disturbance in Indonesia: How Much Does Smoking Contribute?
Published in Behavioral Sleep Medicine, 2020
There exist a number of possible explanations for the association between smoking and sleep disturbance observed in this study. First, at the molecular level, nicotine stimulates neurotransmitters that affect sleep; it is thus possible that continued exposure to this stimulant would lead to sleep disturbance (Zhang et al., 2006). Nicotine stimulates nicotinic acetylcholine receptors in the brain and results in the release of a variety of neurotransmitters in the brain, most importantly dopamine. Based on these effects, nicotine could interact with sleep regulating mechanisms and may contribute to sleep disturbance (Dugas et al., 2017; Jaehne et al., 2012). At the physiological level, nicotine withdrawal symptoms have been associated with sleep disturbance (Staner, Luthringer, Dupont, Aubin, & Lagrue, 2006). It is plausible that some smokers experience nicotine withdrawal in their attempts to quit or during the course of sleep, possibly inducing sleep disturbances. Behavioral variables may also contribute to poorer sleep among cigarette smokers (Fidler & West, 2009). Since smokers often report using cigarette smoking as a form of stress relief and given that smokers self-report more daily stress than nonsmokers, it is possible that stress levels are the underlying cause of their sleep disturbances.
The role of sugammadex, a novel cyclodextrin compound in modern anesthesia practice: conventional neuromuscular physiology and clinical pharmacology
Published in Expert Review of Clinical Pharmacology, 2019
Alan D. Kaye, Rachel J. Kaye, Elyse M. Cornett, Ivan Urits, Vwaire Orhurhu, Omar Viswanath, Amit Prabhakar
As a review of human physiology, the neuromuscular junction is comprised of several key components, including the presynaptic nerve terminal, synaptic cleft, and the post-synaptic nicotinic acetylcholine receptors on motor end-plates [2]. Action potentials propagated along the presynaptic neuron result in the release of acetylcholine into the synaptic cleft. These molecules then bind to two alpha subunits of the ionic post-junctional nicotinic acetylcholine receptors. Binding results in a conformational change in the ion channel prompting an influx of sodium and efflux of potassium. Dosing for neuromuscular blocker agents is typically based on an effective dose (ED) 95, which is the dose in which 95% twitch depression occurs in 50% of individuals [3]. For induction, one, two or three times the ED95 dose is typically administered and for maintenance dosing, the ED95 dosage is employed [3].