scholarly journals Mutual Enhancement of Opioid and Adrenergic Receptors by Combinations of Opioids and Adrenergic Ligands Is Reflected in Molecular Complementarity of Ligands: Drug Development Possibilities

2019 ◽  
Vol 20 (17) ◽  
pp. 4137 ◽  
Author(s):  
Root-Bernstein ◽  
Churchill ◽  
Turke ◽  
Subhramanyam ◽  
Labahn
Keyword(s):  
Adrenergic Receptors ◽  
The Other ◽  
Extracellular Loops ◽  
Allosteric Mechanism ◽  
Combination Drugs ◽  
Second Messenger Systems ◽  
Tethered Compounds ◽  
Compound Type ◽  
Receptor Crosstalk ◽  
Molecular Complementarity

Crosstalk between opioid and adrenergic receptors is well characterized and due to interactions between second messenger systems, formation of receptor heterodimers, and extracellular allosteric binding regions. Both classes of receptors bind both sets of ligands. We propose here that receptor crosstalk may be mirrored in ligand complementarity. We demonstrate that opioids bind to adrenergic compounds with micromolar affinities. Additionally, adrenergic compounds bind with micromolar affinities to extracellular loops of opioid receptors while opioids bind to extracellular loops of adrenergic receptors. Thus, each compound type can bind to the complementary receptor, enhancing the activity of the other compound type through an allosteric mechanism. Screening for ligand complementarity may permit the identification of other mutually-enhancing sets of compounds as well as the design of novel combination drugs or tethered compounds with improved duration and specificity of action.

Receiving the Synaptic Message

2017 ◽  
Author(s):  
Peggy Mason
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Adrenergic Receptors ◽  
Acetylcholine Receptors ◽  
G Protein Coupled Receptors ◽  
Metabotropic Receptors ◽  
Second Messenger Systems ◽  
Psychotropic Effects ◽  
G Protein Coupled ◽  
Ionotropic And Metabotropic Receptors

Ionotropic and metabotropic receptors differ in their speed of action, the variety of effects produced after ligand-binding, and in the number of types present in the nervous system. The participation of two ionotropic glutamate receptors in synaptic plasticity is thought to be the cellular basis of learning. The actions of acetylcholine on nicotinic acetylcholine receptors present at the neuromuscular junction are described. The pharmacological profile of the GABAA receptor, central to most neural functions, is introduced. The properties of metabotropic receptors that are coupled to G proteins, termed G protein-coupled receptors (GPCRs), are detailed. Three canonical second-messenger systems through which GPCRs act are briefly described. An introduction to clinical pharmacology focused on how drugs acting on muscarinic and adrenergic receptors produce peripheral and central psychotropic effects is provided. Finally, the role of connexins and gap junctions in myelination and hearing is introduced.

Hyperinsulinemia in rats with hypothalamic obesity: effects of autonomic drugs and glucose

1983 ◽  
Vol 245 (3) ◽  
pp. R372-R378 ◽  
Author(s):  
S. Inoue ◽  
Y. S. Mullen ◽  
G. A. Bray
Keyword(s):  
Adrenergic Receptors ◽  
Serum Insulin ◽  
The Other ◽  
Glucose Stimulation ◽  
Hypothalamic Obesity ◽  
Insulin Levels ◽  
Alpha Adrenergic Receptors ◽  
Beta Receptors ◽  
Increased Sensitivity ◽  
Stimulation Of

The present study examined the effects of autonomic drugs and glucose on the insulin and glucose concentrations of sham-operated rats and of rats with ventromedial hypothalamic (VMH) lesions and obesity. In the basal condition both epinephrine and atropine significantly decreased serum insulin levels in VMH-lesioned but not sham-operated rats. During glucose stimulation of insulin secretion in VMH-lesioned rats, epinephrine inhibited the increase of insulin by 83% and atropine inhibited it by 42%; whereas in sham-operated rats, epinephrine inhibited it by 70% and atropine inhibited it by 34%. Epinephrine with atropine completely blocked the increase of insulin in response to glucose in both VMH-lesioned and sham-operated rats. In the basal condition, epinephrine together with propranolol significantly decreased serum insulin levels in VMH-lesioned but not sham-operated rats. Epinephrine with phentolamine, on the other hand, markedly increased insulin in the VMH-lesioned rats and to a lesser degree in the sham-operated rats. During glucose stimulation epinephrine with propranolol inhibited the increase of insulin in both groups. Epinephrine with phentolamine or isoproterenol markedly increased serum insulin in VMH-lesioned rats. These results suggest that stimulation of the vagus nerve and increased sensitivity of the beta-receptors on the beta-cells of the islet contribute to the development of hyperinsulinemia. The sympathetic contribution may also be through suppression of alpha-adrenergic receptors.

scholarly journals Co-Evolution of Opioid and Adrenergic Ligands and Receptors: Shared, Complementary Modules Explain Evolution of Functional Interactions and Suggest Novel Engineering Possibilities

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1217
Author(s):  
Robert Root-Bernstein ◽  
Beth Churchill
Keyword(s):  
Ligand Binding ◽  
Experimental Evidence ◽  
Opioid Receptors ◽  
Adrenergic Receptors ◽  
Functional Modules ◽  
Functional Interactions ◽  
Evolutionary Origins ◽  
Second Messenger Systems ◽  
Binding Regions ◽  
Transmembrane Regions

Cross-talk between opioid and adrenergic receptors is well-characterized and involves second messenger systems, the formation of receptor heterodimers, and the presence of extracellular allosteric binding regions for the complementary ligand; however, the evolutionary origins of these interactions have not been investigated. We propose that opioid and adrenergic ligands and receptors co-evolved from a common set of modular precursors so that they share binding functions. We demonstrate the plausibility of this hypothesis through a review of experimental evidence for molecularly complementary modules and report unexpected homologies between the two receptor types. Briefly, opioids form homodimers also bind adrenergic compounds; opioids bind to conserved extracellular regions of adrenergic receptors while adrenergic compounds bind to conserved extracellular regions of opioid receptors; opioid-like modules appear in both sets of receptors within key ligand-binding regions. Transmembrane regions associated with homodimerization of each class of receptors are also highly conserved across receptor types and implicated in heterodimerization. This conservation of multiple functional modules suggests opioid–adrenergic ligand and receptor co-evolution and provides mechanisms for explaining the evolution of their crosstalk. These modules also suggest the structure of a primordial receptor, providing clues for engineering receptor functions.

scholarly journals Ligand-specific conformational change drives interdomain allostery in Pin1

2021 ◽  
Author(s):  
Beat Vogeli ◽  
Alexandra Born ◽  
Janne Soetbeer ◽  
Morkos Henen ◽  
Frauke Breitgoff ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Ligand Binding ◽  
Conformational Change ◽  
Conformational Changes ◽  
Catalytic Domain ◽  
Catalytic Site ◽  
The Other ◽  
Allosteric Mechanism ◽  
Catalytic Loop ◽  
Extended States

Abstract Pin1 is a two-domain cell regulator that isomerizes peptidyl-prolines. The catalytic domain (PPIase) and the other ligand-binding domain (WW) sample extended and compact conformations. Ligand binding changes the equilibrium of the interdomain conformations, but the conformational changes that lead to the altered domain sampling were unknown. Prior evidence has supported an interdomain allosteric mechanism. We recently introduced a magnetic resonance-based protocol that allowed us to determine the coupling of intra- and interdomain structural sampling in apo Pin1. Here, we describe ligand-specific conformational changes that occur upon binding of pCDC25c and FFpSPR. pCDC25c binding doubles the population of the extended states compared to the virtually identical populations of the apo and FFpSPR-bound forms. pCDC25c binding to the WW domain triggers conformational changes to propagate via the interdomain interface to the catalytic site, while FFpSPR binding displaces a helix in the PPIase that leads to repositioning of the PPIase catalytic loop.

scholarly journals Comparison of the inhibition of insulin release by activation of adenosine and α2-adrenergic receptors in rat β-cells

1989 ◽  
Vol 259 (1) ◽  
pp. 223-228 ◽  
Author(s):  
G Bertrand ◽  
M Nenquin ◽  
J C Henquin
Keyword(s):  
Protein Kinase C ◽  
Adenylate Cyclase ◽  
Insulin Release ◽  
Adrenergic Receptors ◽  
Inhibitory Effect ◽  
The Other ◽  
Complete Inhibition ◽  
Dibutyryl Cyclic Amp ◽  
Β Cells ◽  
Kinase C

Rat islets were used to compare the mechanisms whereby adenosine and adrenaline inhibit insulin release. Adenosine (1 microM-2.5 mM) and its analogue N6(-)-phenylisopropyladenosine (L-PIA) (1 nM-10 microM) caused a concentration-dependent but incomplete (45-60%) inhibition of glucose-stimulated release. L-PIA was more potent than D-PIA [the N6(+) analogue], but much less than adrenaline, which caused nearly complete inhibition (85% at 0.1 microM). 8-Phenyltheophylline prevented the inhibitory effect of L-PIA and 50 microM-adenosine, but not that of 500 microM-adenosine or of adrenaline. In contrast, yohimbine selectively prevented the inhibition by adrenaline. Adenosine and L-PIA thus appear to exert their effects by activating membrane A1 receptors, whereas adrenaline acts on alpha 2-adrenergic receptors. Adenosine, L-PIA and adrenaline slightly inhibited 45Ca2+ efflux, 86Rb+ efflux and 45Ca2+ influx in glucose-stimulated islets. The inhibition of insulin release by adenosine or L-PIA was totally prevented by dibutyryl cyclic AMP, but was only attenuated when adenylate cyclase was activated by forskolin or when protein kinase C was stimulated by a phorbol ester. Adrenaline, on the other hand, inhibited release under these conditions. It is concluded that inhibition of adenylate cyclase, rather than direct changes in membrane K+ and Ca2+ permeabilities, underlies the inhibition of insulin release induced by activation of A1-receptors. The more complete inhibition mediated by alpha 2-adrenergic receptors appears to result from a second mechanism not triggered by adenosine.

Arachidonate Metabolism And Platelet Disaggregation (DA)-Reaggregation (RA)

1981 ◽  
Author(s):  
Gundu H R Rao ◽  
James G White
Keyword(s):  
Platelet Aggregation ◽  
Adrenergic Receptors ◽  
Thromboxane A2 ◽  
The Other ◽  
Inhibit Platelet Aggregation ◽  
Activated Platelets ◽  
Arachidonate Metabolism ◽  
Thromboxane Synthetase ◽  
Platelet Disaggregation ◽  
Refractory State

Previous work has shown that platelets irreversibly aggregated by ADP or thrombin (T) can be dissociated by various agents and that the refractory state of disaggregated cells can be reversed immediately by treatment with epinephrine (E). In the present study we have evaluated the influence of drugs which affect different steps in the process of prostaglandin (PG) synthesis on platelet DA-RA. Aspirin and indomethacin did not cause DA of platelets in the process of aggregation nor did they prevent reversal of the refractory state by E and subsequent RA of previously dissociated platelets. Imidazole, which inhibits conversion of endoperoxide to thromboxane A2, also failed to influence DA or restoration of sensitvity and RA of disaggregated platelets. On the other hand, chemicals which interfere with release of AA from the membrane of activated platelets, such as mepacrine, chlorpromazine and trifluoperazine, caused rapid DA. Products of PG synthesis, such as PGE1, PGD2 and PGI2, which usually inhibit platelet aggregation, also caused rapid DA. The refractory state of platelets dissociated from aggregates by most of these agents could be reversed by E treatment. However, trifluoperazine disaggregated platelets could be reaggregated only by the combination of E and AA. Agents which block the a-adrenergic receptors did not cause dissociation of aggregating platelets, but prevented correction of the refractory state of dissociated platelets by E. Thus interference with AA release, even after aggregation, can cause DA of clumped platelets, but blockade of peroxidase, cyclo-oxygenase and thromboxane synthetase do not cause reversal once it is in progress. A membrane linked mechanism associated with AA availability, but not metabolism, regulates DA and restoration of membrane sensitivity for RA.

scholarly journals Xylometazoline and oxymetazoline - unusual effects of everyday drugs (literature review)

2021 ◽  
Vol 11 (9) ◽  
pp. 272-281
Author(s):  
Jakub Klas ◽  
Natalia Kluz ◽  
Klaudia Piwowar
Keyword(s):  
Side Effects ◽  
Adrenergic Receptors ◽  
Lower Respiratory Tract ◽  
The Other ◽  
Angina Attack ◽  
Nasal Sprays ◽  
Drug List ◽  
Imidazoline Derivatives ◽  
Carious Lesions ◽  
Pharmacological Potential

The aim of the study is to systematize the knowledge about xylometazoline and oxymetazoline - commonly used nasal sprays with sympathicomimetic effect, mainly directly on α-adrenergic receptors [1]. A review of recent reports on possible side effects and new therapeutic options will be presented. Results: Over several years, reports have been published regarding descriptions of unusual cases of side effects, such as angina attack [4], a case of respiratory failure in a newborn [5], ischemic stroke [6], or anaphylactic reaction during routine surgery. In experiments using rats, on the other hand, it has been shown that these substances can also cause increased inflammation of the lower respiratory tract [7], as well as numerous ophthalmic problems [8]. Recent reports also suggest new uses for xylometazoline and oxymetazoline. In combination with lidocaine, an intranasal solution of xylometazoline has shown efficacy in the anesthesia of maxillary teeth in patients with minor carious lesions [9], and a beneficial therapeutic combination of oxymetazoline and dye laser (PDL) has also been reported for the treatment of rosacea, among others [10]. Conclusions: Although imidazoline derivatives were admitted to the drug list decades ago, still their pharmacological potential has not been fully exploited. Finding applications of these drugs in dermatology and dentistry may not only improve the efficacy and comfort of treatment, but also significantly reduce the costs of the whole therapy. The aforementioned reports on the side effects of xylometazoline and oxymetazoline should not be forgotten. It is possible that the presented examples will increase awareness to use these drugs with more respect, according to the recommendations on the leaflet.

scholarly journals Structural basis for Ca2+ activation of the heteromeric PKD1L3/PKD2L1 channel

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qiang Su ◽  
Mengying Chen ◽  
Yan Wang ◽  
Bin Li ◽  
Dan Jing ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Binding Site ◽  
The Other ◽  
Structural Basis ◽  
Polycystic Kidney ◽  
Channel Activation ◽  
Allosteric Mechanism ◽  
Voltage Sensing Domain ◽  
Pore Domain

AbstractThe heteromeric complex between PKD1L3, a member of the polycystic kidney disease (PKD) protein family, and PKD2L1, also known as TRPP2 or TRPP3, has been a prototype for mechanistic characterization of heterotetrametric TRP-like channels. Here we show that a truncated PKD1L3/PKD2L1 complex with the C-terminal TRP-fold fragment of PKD1L3 retains both Ca2+ and acid-induced channel activities. Cryo-EM structures of this core heterocomplex with or without supplemented Ca2+ were determined at resolutions of 3.1 Å and 3.4 Å, respectively. The heterotetramer, with a pseudo-symmetric TRP architecture of 1:3 stoichiometry, has an asymmetric selectivity filter (SF) guarded by Lys2069 from PKD1L3 and Asp523 from the three PKD2L1 subunits. Ca2+-entrance to the SF vestibule is accompanied by a swing motion of Lys2069 on PKD1L3. The S6 of PKD1L3 is pushed inward by the S4-S5 linker of the nearby PKD2L1 (PKD2L1-III), resulting in an elongated intracellular gate which seals the pore domain. Comparison of the apo and Ca2+-loaded complexes unveils an unprecedented Ca2+ binding site in the extracellular cleft of the voltage-sensing domain (VSD) of PKD2L1-III, but not the other three VSDs. Structure-guided mutagenic studies support this unconventional site to be responsible for Ca2+-induced channel activation through an allosteric mechanism.

Stromatoporoids from the Famennian (Devonian) Wabamun Formation, Normandville oilfield, north–central Alberta, Canada

1988 ◽  
Vol 62 (03) ◽  
pp. 411-419 ◽  
Author(s):  
Colin W. Stearn
Keyword(s):  
Patch Reef ◽  
Abundant Species ◽  
The Other ◽  
North Central ◽  
Biotic Crisis

Stromatoporoids are the principal framebuilding organisms in the patch reef that is part of the reservoir of the Normandville field. The reef is 10 m thick and 1.5 km2in area and demonstrates that stromatoporoids retained their ability to build reefal edifices into Famennian time despite the biotic crisis at the close of Frasnian time. The fauna is dominated by labechiids but includes three non-labechiid species. The most abundant species isStylostroma sinense(Dong) butLabechia palliseriStearn is also common. Both these species are highly variable and are described in terms of multiple phases that occur in a single skeleton. The other species described areClathrostromacf.C. jukkenseYavorsky,Gerronostromasp. (a columnar species), andStromatoporasp. The fauna belongs in Famennian/Strunian assemblage 2 as defined by Stearn et al. (1988).

D. The Line Spectrum of Pulsating Variable Stars

1967 ◽  
Vol 28 ◽  
pp. 207-244
Author(s):  
R. P. Kraft
Keyword(s):  
Variable Stars ◽  
The Other ◽  
Line Spectrum ◽  
Afternoon Session ◽  
Empirical Information ◽  
Pulsating Variable Stars ◽  
Almost Continuous ◽  
Informal Approach

(Ed. note:Encouraged by the success of the more informal approach in Christy's presentation, we tried an even more extreme experiment in this session, I-D. In essence, Kraft held the floor continuously all morning, and for the hour and a half afternoon session, serving as a combined Summary-Introductory speaker and a marathon-moderator of a running discussion on the line spectrum of cepheids. There was almost continuous interruption of his presentation; and most points raised from the floor were followed through in detail, no matter how digressive to the main presentation. This approach turned out to be much too extreme. It is wearing on the speaker, and the other members of the symposium feel more like an audience and less like participants in a dissective discussion. Because Kraft presented a compendious collection of empirical information, and, based on it, an exceedingly novel series of suggestions on the cepheid problem, these defects were probably aggravated by the first and alleviated by the second. I am much indebted to Kraft for working with me on a preliminary editing, to try to delete the side-excursions and to retain coherence about the main points. As usual, however, all responsibility for defects in final editing is wholly my own.)

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