scholarly journals Importance and prospects for design of selective muscarinic agonists

2008 ◽  
pp. S39-S47
Author(s):  
J Jakubík ◽  
P Michal ◽  
E Machová ◽  
V Doležal
Keyword(s):  
Binding Sites ◽  
Natural Aging ◽  
Receptor Activation ◽  
Receptor Subtypes ◽  
Muscarinic Agonists ◽  
Amyloidogenic Processing ◽  
M1 Receptor ◽  
The Central Nervous System ◽  
M1 Agonist ◽  
Stimulation Of

There are five subtypes of muscarinic receptors that serve various important physiological functions in the central nervous system and the periphery. Mental functions like attention, learning, and memory are attributed to the muscarinic M1 subtype. These functions decline during natural aging and an early deficit is typical for Alzheimer s disease. In addition, stimulation of the M1 receptor increases non-amyloidogenic processing of the amyloid precursor protein and thus prevents accumulation of noxious beta-amyloid fragments. The selectivity of classical muscarinic agonists among receptor subtypes is very low due to the highly conserved nature of the orthosteric binding site among receptor subtypes. Herein we summarize some recent studies with the functionally-selective M1 agonist xanomeline that indicate complex pharmacological profile of this drug that includes interactions with and activation of receptor from both orthosteric and ectopic binding sites, and the time-dependent changes of ligand binding and receptor activation. These findings point to potential profitability of exploitation of ectopic ligands in the search for truly selective muscarinic receptor agonists.

The Role of 5–Hydroxytryptamine (5–HT) Receptor Subtypes and Plasticity in the 5–HT Systems in the Regulation of Nociceptive Sensitivity

Cephalalgia ◽  
1993 ◽  
Vol 13 (2) ◽  
pp. 75-85 ◽  
Author(s):  
Per Kristian Eide ◽  
Kjell Hole
Keyword(s):  
Receptor Activation ◽  
Term Treatment ◽  
Receptor Subtypes ◽  
Functional Changes ◽  
Nociceptive Sensitivity ◽  
Denervation Supersensitivity ◽  
Long Term Treatment ◽  
Stimulation Of

This review shows that the role of 5–hydroxytryptamine (5–HT) in the regulation of nociception depends on the 5–HT receptor subtypes involved and on long-term functional changes in the 5–HT receptors. Stimulation of the 5–HT 1 receptors, as well as of the 5–HT 2 and 5–HT 3 receptors, may reduce nociceptive sensitivity. In addition, activation of 5–HT 2 and 5–HT 3 receptors may also enhance nociceptive sensitivity. Up- or down-regulation of the 5–HT receptors may result in long-lasting changes, plasticity, in the 5–HT systems. Lesioning of 5–HT neurons induces denervation supersensitivity to 5–HT, and prolonged stimulation of 5–HT receptors may produce subsensitivity to 5–HT. In the spinal cord denervation supersensitivity to 5–HT may depend on reduced release of substance P (SP). An increase in the release of SP, on the other hand, may reduce the effects of 5–HT receptor activation. Long-term treatment with antidepressants which are used in clinical pain therapy appears to up-regulate the 5–HT 1 receptors and to down-regulate the 5–HT 2 receptors.

A P2X7 receptor stimulates plasma membrane trafficking in the FRTL rat thyrocyte cell line

2004 ◽  
Vol 287 (4) ◽  
pp. C992-C1002 ◽  
Author(s):  
M. Y. Kochukov ◽  
A. K. Ritchie
Keyword(s):  
Plasma Membrane ◽  
Cell Line ◽  
Fluorescence Imaging ◽  
Receptor Activation ◽  
Disulfonic Acid ◽  
Receptor Subtypes ◽  
Patch Clamp Recording ◽  
Thyroid Cells ◽  
Rat Thyroid ◽  
Stimulation Of

Thyroid cells express a variety of P2Y and P2X purinergic receptor subtypes. G protein-coupled P2Y receptors influence a wide variety of thyrocyte-specific functions; however, functional P2X receptor-gated channels have not been observed. In this study, we used whole cell patch-clamp recording and fluorescence imaging of the plasma membrane marker FM1-43 to examine the effects of extracellular ATP on membrane permeability and trafficking in the Fisher rat thyroid cell line FRTL. We found a cation-selective current that was gated by ATP and 2′,3′- O-(4-benzoylbenzoyl)-ATP but not by UTP. The ATP-evoked currents were inhibited by pyridoxal phosphate 6-azophenyl-2′,4′-disulfonic acid, adenosine 5′-triphosphate-2′,3′-dialdehyde, 100 μM Zn2+, and 50 μM Cu2+. Fluorescence imaging revealed pronounced, temperature-sensitive stimulation of exocytosis and membrane internalization by ATP with the same pharmacological profile as observed for activation of current. The EC50 for ATP stimulation of internalization was 440 μM in saline containing 2 mM Ca2+ and 2 mM Mg2+, and 33 μM in low-Mg2+, nominally Ca2+-free saline. Overall, the results are most consistent with activation of a P2X7 receptor by ATP4−. However, low permeability to N-methyl-d-glucamine+ and the propidium cation YO-PRO-1 indicates absence of the cytolytic pore that often accompanies P2X7 receptor activation. ATP stimulation of internalization occurs in Na+-free, Ca2+-free, or low-Mg2+ saline and therefore does not depend on cation influx through the ATP-gated channel. We conclude that ATP activation of a P2X7 receptor stimulates membrane internalization in FRTL cells via a transduction pathway that does not depend on cation influx.

Stimulation of acid secretion and phosphoinositol production by rat parietal cell muscarinic M2 receptors

1988 ◽  
Vol 254 (4) ◽  
pp. G622-G629
Author(s):  
A. Pfeiffer ◽  
H. Rochlitz ◽  
A. Herz ◽  
G. Paumgartner
Keyword(s):  
Acid Secretion ◽  
Muscarinic Receptor ◽  
Inositol Phosphates ◽  
Inositol Phosphate ◽  
Receptor Activation ◽  
Receptor Subtype ◽  
Muscarinic Agonists ◽  
Receptor System ◽  
Drug Concentrations ◽  
Stimulation Of

The muscarinic receptor system involved in hydrogen ion production by enriched rat gastric parietal cells was investigated. Muscarinic receptor density determined by [N-methyl-3H]scopolamine binding was 8,100/cell. The receptor appeared to be of the M2 muscarinic receptor subtype, since it had a low affinity (Kd, 189 nM) for the M1 receptor antagonist pirenzepine compared with atropine (Kd, 0.74 nM). Receptor activation by carbachol rapidly augmented levels of polyphosphoinositides, indicating an activation of a phospholipase C. The dose-response relations for the increase in inositol phosphates closely paralleled the binding of carbachol to muscarinic receptors with a Km of 17 microM. The inositol phosphate response was antagonized by pirenzepine with a Ki of 177 nM. The stimulation of inositol phosphate levels by carbachol correlated well with the stimulation of [14C]aminopyrine uptake, determined as an index of acid secretion. The muscarinic agonists oxotremorine, pilocarpine, and bethanechol elicited partial increases in inositol phosphates at maximal drug concentrations, and these partial increases correlated with their ability to stimulate [14C]aminopyrine uptake. These data indicate that inositol polyphosphates may be a second messenger of M2 receptors stimulating acid secretion.

The dopamine receptor in adult and maturing kidney

1989 ◽  
Vol 257 (3) ◽  
pp. F315-F327 ◽  
Author(s):  
R. A. Felder ◽  
C. C. Felder ◽  
G. M. Eisner ◽  
P. A. Jose
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Adenylate Cyclase ◽  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Receptor Activation ◽  
Receptor Subtypes ◽  
The Central Nervous System ◽  
Renal Tubular ◽  
Da2 Receptor

Dopamine, like other neurotransmitters, exerts its biological effects by occupation of specific receptor subtypes. The dopamine receptors in the central nervous system and certain endocrine organs are classified into the D1/D2 subtypes. Outside the central nervous system, the dopamine receptors are classified into the DA1/DA2 subtypes. The D1/D2 and DA1/DA2 receptor have marked similarities and some differences, the most notable of which is the lower affinity of the DA dopamine compared with the D dopamine receptor. DA1 receptor activation increases renal blood flow (RBF); stimulation of DA1 and DA2 receptors may also increase glomerular filtration rate (GFR). DA1 agonists inhibit fluid and electrolyte transport indirectly via hemodynamic mechanisms and directly by occupation of DA1 receptors in specific nephron segments. In the proximal tubule, DA1 agonists simulate adenylate cyclase and inhibit Na+-H+ antiport activity. They also increase phospholipase C and inhibit Na+-K+-ATPase activity (presumably as a consequence of protein kinase C activation). The latter effects may be facilitated by DA2 agonists. In cortical collecting ducts, dopamine antagonizes the effects of mineralocorticoids and the hydrosomotic effect of antidiuretic hormone. It has also been suggested that DA1 may also decrease sodium transport by influencing other hormones, such as atrial natriuretic peptide. Studies of dopamine in the young are complicated because of the propensity for dopamine to stimulate alpha-adrenoceptors. Dopamine alone may actually decrease RBF in the perinatal period. In some animals, the renal vasodilatory and natriuretic effects of dopamine increase with age. Renal tubular DA1-stimulated adenylate cyclase activity increases, whereas renal tubular DA1 receptors decrease with age. Renal DA2 receptor density is greater in the fetus; after birth renal DA2 receptors do not change. Endogenous dopamine may regulate sodium excretion in the young differently than in the adult. In the adult, sodium surfeit is associated with an increase in urinary dopamine; the opposite occurs in the young. A decrease in dopamine production or blockade of dopamine receptors results in an antinatriuresis in the adult; dopamine blockade in the young results in a natriuresis. It remains to be determined whether these age-related differences in dopamine effects are due to changes in receptor DA subtype density, second messengers, and/or interaction with other receptors.

scholarly journals Nicotinic modulation insecticides act on diverse receptor subtypes with distinct subunit compositions

2021 ◽  
Author(s):  
Wanjun Lu ◽  
Zhihan Liu ◽  
Xinyu Fan ◽  
Xinzhong Zhang ◽  
Xiaomu Qiao ◽  
...  
Keyword(s):  
Ion Channels ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Resistance Management ◽  
Receptor Activation ◽  
Receptor Subtypes ◽  
Resistance Development ◽  
The Central Nervous System ◽  
Negative Impacts

Insect nicotinic acetylcholine receptors (nAChRs) are ligand gated ion channels mainly expressed in the central nervous system of insects. They are the directed targets of nicotinic modulation insecticides including neonicotinoids, the most widely used insecticides in the world. However, the resistance development from pests and the negative impacts on the pollinators affect their applications and create demand for the alternatives. Thus, it is very important to understand the mode of action of these insecticides at the molecular level, which is actually unclear for more than 30 years. In this study, we systematically examined the susceptibility of ten Drosophila melanogaster nAChR subunits mutants against eleven nicotinic modulation insecticides. Our results showed that there are several subtypes of nAChRs with distinct subunits compositions that are responsible for the toxicity of different insecticides, respectively. At least three of them are the major molecular targets of seven structurally similar neonicotinoids in vivo. On the other hand, the spinosyns may exclusively act on the α6 homomeric nAChR but not any other heteromeric pentamers. Behavioral assays using thermogenetic tools further confirmed the bioassay results and support the idea that receptor activation rather than inhibition leads to the insecticidal effects of neonicotinoids. The present findings reveal native nAChR subunit interactions with various insecticides and have important implications for resistance management and the development of novel insecticides targeting this important ion channels.

GABAA receptors: Various stoichiometrics of subunit arrangement in α1β3 and α1β3ε receptors

2018 ◽  
Vol 24 (17) ◽  
pp. 1839-1844 ◽  
Author(s):  
Ahmad Tarmizi Che Has ◽  
Mary Chebib
Keyword(s):  
Central Nervous System ◽  
Gabaa Receptors ◽  
Binding Sites ◽  
New Drugs ◽  
Pharmacological Properties ◽  
Receptor Complex ◽  
The Third ◽  
Γ Subunit ◽  
Subunit Stoichiometry ◽  
The Central Nervous System

GABAA receptors are members of the Cys-loop family of ligand-gated ion channels which mediate most inhibitory neurotransmission in the central nervous system. These receptors are pentameric assemblies of individual subunits, including α1-6, β1-3, γ1-3, δ, ε, π, θ and ρ1-3. The majority of receptors are comprised of α, β and γ or δ subunits. Depending on the subunit composition, the receptors are located in either the synapses or extrasynaptic regions. The most abundant receptors are α1βγ2 receptors, which are activated and modulated by a variety of pharmacologically and clinically unrelated agents such as benzodiazepines, barbiturates, anaesthetics and neurosteroids, all of which bind at distinct binding sites located within the receptor complex. However, compared to αβγ, the binary αβ receptors lack a benzodiazepine α-γ2 interface. In pentameric αβ receptors, the third subunit is replaced with either an α1 or a β3 subunit leading to two distinct receptors that differ in subunit stoichiometry, 2α:3β or 3α:2β. The consequence of this is that 3α:2β receptors contain an α-α interface whereas 2α:3β receptors contain a β-β interface. Apart from the replacement of γ by α1 or β3 in binary receptors, the incorporation of ε subunit into GABAA receptors might be more complicated. As the ε subunit is not only capable of substituting the γ subunit, but also replacing the α/β subunits, receptors with altered stoichiometry and different pharmacological properties are produced. The different subunit arrangement of the receptors potentially constructs novel binding sites which may become new targets of the current or new drugs.

NMDAR PAMs: Multiple Chemotypes for Multiple Binding Sites

2019 ◽  
Vol 19 (24) ◽  
pp. 2239-2253 ◽  
Author(s):  
Paul J. Goldsmith
Keyword(s):  
Binding Sites ◽  
Receptor Activation ◽  
Research Area ◽  
Allosteric Modulators ◽  
Nonselective Cation Channels ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Excitatory Neurotransmission ◽  
Psychiatric Conditions ◽  
High Level

The N-methyl-D-aspartate receptor (NMDAR) is a member of the ionotropic glutamate receptor (iGluR) family that plays a crucial role in brain signalling and development. NMDARs are nonselective cation channels that are involved with the propagation of excitatory neurotransmission signals with important effects on synaptic plasticity. NMDARs are functionally and structurally complex receptors, they exist as a family of subtypes each with its own unique pharmacological properties. Their implication in a variety of neurological and psychiatric conditions means they have been a focus of research for many decades. Disruption of NMDAR-related signalling is known to adversely affect higherorder cognitive functions (e.g. learning and memory) and the search for molecules that can recover (or even enhance) receptor output is a current strategy for CNS drug discovery. A number of positive allosteric modulators (PAMs) that specifically attempt to overcome NMDAR hypofunction have been discovered. They include various chemotypes that have been found to bind to several different binding sites within the receptor. The heterogeneity of chemotype, binding site and NMDAR subtype provide a broad landscape of ongoing opportunities to uncover new features of NMDAR pharmacology. Research on NMDARs continues to provide novel mechanistic insights into receptor activation and this review will provide a high-level overview of the research area and discuss the various chemical classes of PAMs discovered so far.

Central Histamine, the H3-Receptor and Obesity Therapy

2019 ◽  
Vol 18 (7) ◽  
pp. 516-522
Author(s):  
Néstor F. Díaz ◽  
Héctor Flores-Herrera ◽  
Guadalupe García-López ◽  
Anayansi Molina-Hernández
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Animal Studies ◽  
Energy Homeostasis ◽  
Receptor Activation ◽  
Receptor Ligands ◽  
Histaminergic System ◽  
H3 Receptor ◽  
Weight One ◽  
The Central Nervous System

The brain histaminergic system plays a pivotal role in energy homeostasis, through H1- receptor activation, it increases the hypothalamic release of histamine that decreases food intake and reduces body weight. One way to increase the release of hypothalamic histamine is through the use of antagonist/inverse agonist for the H3-receptor. Histamine H3-receptors are auto-receptors and heteroreceptors located on the presynaptic membranes and cell soma of neurons, where they negatively regulate the synthesis and release of histamine and other neurotransmitters in the central nervous system. Although several compounds acting as H3-receptor antagonist/inverse agonists have been developed, conflicting results have been reported and only one has been tested as anti-obesity in humans. Animal studies revealed the opposite effect in food intake, energy expeditor, and body weight, depending on the drug, spice, and route of administration, among others. The present review will explore the state of art on the effects of H3-receptor ligands on appetite and body-weight, going through the following: a brief overview of the circuit involved in the control of food intake and energy homeostasis, the participation of the histaminergic system in food intake and body weight, and the H3-receptor as a potential therapeutic target for obesity.

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