Andrew J Irving’s research while affiliated with University of Dundee and other places

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Publications (96)


GPR18, GPR55 and GPR119 in GtoPdb v.2023.1
  • Article
  • Full-text available

April 2023

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35 Reads

IUPHAR/BPS Guide to Pharmacology CITE

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Andrew J. Irving

GPR18, GPR55 and GPR119 (provisional nomenclature), although showing little structural similarity to CB1 and CB2 cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [104]. Although there are multiple reports to indicate that GPR18, GPR55 and GPR119 can be activated in vitro by N-arachidonoylglycine, lysophosphatidylinositol and N-oleoylethanolamide, respectively, there is a lack of evidence for activation by these lipid messengers in vivo. As such, therefore, these receptors retain their orphan status.

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Fig. 1 (See legend on previous page.)
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Fig. 5 GPER1 is involved in activity-dependent LTP at TA-CA1 synapses. A-D Plots of pooled data illustrating effects on synaptic transmission at juvenile TA-CA1 synapses. A Delivery of HFS (shown by arrow) resulted in the induction of LTP, however subsequent addition of G1 failed to alter synaptic transmission. B Application of G1 induced cLTP, but subsequent delivery of HFS failed to increase synaptic transmission further. Activity-dependent LTP and GPER1-induced LTP share analogous expression mechanisms. C In control slices, HFS readily induced LTP. D In interleaved slices exposed to the GPER1 antagonist, G15 (200 nM), delivery of HFS failed to induce LTP. GPER1 activation is involved in activity-dependent LTP
Fig. 6 GPER1 activation results in induction of a novel form of NMDA receptor dependent LTP at juvenile TA-CA1 synapses. Schematic representation of the cellular events contributing to the induction of a novel form of LTP induced by activation of GPER1. Treatment with the selective GPER1 agonist, G1 or endogenous E2 results in the activation of GPER1 and stimulation of ERK-dependent signalling. This leads to activation of synaptic GluN2A-containing NMDA receptors and trafficking of GluA2-lacking AMPA receptors into hippocampal TA-CA1 synapses which in turn causes a persistent increase in synaptic efficacy. In parallel, E2 is also capable of activating ERα, which also promotes synaptic insertion of GluA2-lacking AMPA receptors and an increase in TA-CA1 synaptic efficacy, via a process involving PI3K-driven signalling and activation of GluN2B-containing NMDA receptors
G-protein coupled estrogen receptor (GPER1) activation promotes synaptic insertion of AMPA receptors and induction of chemical LTP at hippocampal temporoammonic-CA1 synapses

January 2023

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395 Reads

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3 Citations

Molecular Brain

Leigh Clements

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Amy Alexander

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It is well documented that 17β estradiol (E2) regulates excitatory synaptic transmission at hippocampal Shaffer-collateral (SC)-CA1 synapses, via activation of the classical estrogen receptors (ERα and ERβ). Hippocampal CA1 pyramidal neurons are also innervated by the temporoammonic (TA) pathway, and excitatory TA-CA1 synapses are reported to be regulated by E2. Recent studies suggest a role for the novel G-protein coupled estrogen receptor (GPER1) at SC-CA1 synapses, however, the role of GPER1 in mediating the effects of E2 at juvenile TA-CA1 synapses is unclear. Here we demonstrate that the GPER1 agonist, G1 induces a persistent, concentration-dependent (1–10 nM) increase in excitatory synaptic transmission at TA-CA1 synapses and this effect is blocked by selective GPER1 antagonists. The ability of GPER1 to induce this novel form of chemical long-term potentiation (cLTP) was prevented following blockade of N-methyl-d-aspartate (NMDA) receptors, and it was not accompanied by any change in paired pulse facilitation ratio (PPR). GPER1-induced cLTP involved activation of ERK but was independent of phosphoinositide 3-kinase (PI3K) signalling. Prior treatment with philanthotoxin prevented the effects of G1, indicating that synaptic insertion of GluA2-lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors underlies GPER1-induced cLTP. Furthermore, activity-dependent LTP occluded G1‐induced cLTP and vice versa, indicating that these processes have overlapping expression mechanisms. Activity‐dependent LTP was blocked by the GPER1 antagonist, G15, suggesting that GPER1 plays a role in NMDA‐dependent LTP at juvenile TA‐CA1 synapses. These findings add a new dimension to our understanding of GPER1 in modulating neuronal plasticity with relevance to age-related neurodegenerative conditions.


Regulation of hippocampal synaptic function by the metabolic hormone leptin: Implications for health and disease

April 2021

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288 Reads

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28 Citations

Progress in Lipid Research

Significant advances have been made in our understanding of the hormone, leptin and its CNS actions in recent years. It is now evident that leptin has a multitude of brain functions, that extend beyond its established role in the hypothalamic control of energy balance. Additional brain regions including the hippocampus are important targets for leptin, with a high density of leptin receptors (LepRs) expressed in specific hippocampal regions and localised to CA1 synapses. Extensive evidence indicates that leptin has pro-cognitive actions, as it rapidly modifies synaptic efficacy at excitatory Schaffer collateral (SC)-CA1 and temporoammonic (TA)-CA1 synapses and enhances performance in hippocampal-dependent memory tasks. There is a functional decline in hippocampal responsiveness to leptin with age, with significant reductions in the modulatory effects of leptin at SC-CA1 and TA-CA1 synapses in aged, compared to adult hippocampus. As leptin has pro-cognitive effects, this decline in leptin sensitivity is likely to have negative consequences for cognitive function during the aging process. Here we review how evaluation of the hippocampal actions of leptin has improved our knowledge of the regulatory brain functions of leptin in health and provided significant insight into the impact of leptin in age-related neurodegenerative disorders linked to cognitive decline.


N-Palmitoylglycine and other N-acylamides activate the lipid receptor G2A/GPR132

November 2019

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466 Reads

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25 Citations

The G-protein-coupled receptor GPR132, also known as G2A, is activated by 9-hydroxy-octadecadienoic acid (9-HODE) and other oxidized fatty acids. Other suggested GPR132 agonists including lysophosphatidylcholine (LPC) have not been readily reproduced. Here, we identify N-acylamides in particular N-acylglycines, as lipid activators of GPR132 with comparable activity to 9-HODE. The order-of-potency is N-palmitoylglycine > 9-HODE ≈ N-linoleoylglycine > linoleamide > N-oleoylglycine ≈ N-stereoylglycine > N-arachidonoyl-glycine > N-docosehexanoylglycine. Physiological concentrations of N-acylglycines in tissue are sufficient to activate GPR132. N-linoleoylglycine and 9-HODE also activate rat and mouse GPR132, despite limited sequence conservation to human. We describe pharmacological tools for GPR132, identified through drug screening. SKF-95667 is a novel GPR132 agonist. SB-583831 and SB-583355 are peptidomimetic molecules containing core amino acids (glycine and phenylalanine, respectively), and structurally related to previously described ligands. A telmisartan analog, GSK1820795A, antagonizes the actions of N-acylamides at GPR132. The synthetic cannabinoid CP-55 940 also activates GPR132. Molecular docking to a homology model suggested a site for lipid binding, predicting the acyl side-chain to extend into the membrane bilayer between TM4 and TM5 of GPR132. Small-molecule ligands are envisaged to occupy a "classical" site encapsulated in the 7TM bundle. Structure-directed mutagenesis indicates a critical role for arginine at position 203 in transmembrane domain 5 to mediate GPR132 activation by N-acylamides. Our data suggest distinct modes of binding for small-molecule and lipid agonists to the GPR132 receptor. Antagonists, such as those described here, will be vital to understand the physiological role of this long-studied target.


GPR18, GPR55 and GPR119 (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

September 2019

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40 Reads

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2 Citations

IUPHAR/BPS Guide to Pharmacology CITE

GPR18, GPR55 and GPR119 (provisional nomenclature), although showing little structural similarity to CB1 and CB2 cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [98]. Although there are multiple reports to indicate that GPR18, GPR55 and GPR119 can be activated in vitro by N-arachidonoylglycine, lysophosphatidylinositol and N-oleoylethanolamide, respectively, there is a lack of evidence for activation by these lipid messengers in vivo. As such, therefore, these receptors retain their orphan status.


GPR55 controls functional differentiation of self-renewing epithelial progenitors for salivation

February 2019

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348 Reads

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5 Citations

JCI Insight

GPR55, a lipid-sensing receptor, is implicated in cell cycle control, malignant cell mobilization, and tissue invasion in cancer. However, a physiological role for GPR55 is virtually unknown for any tissue type. Here, we localize GPR55 to self-renewing ductal epithelial cells and their terminally differentiated progeny in both human and mouse salivary glands. Moreover, we find GPR55 expression downregulated in salivary gland mucoepidermoid carcinomas and GPR55 reinstatement by antitumor irradiation, suggesting that GPR55 controls renegade proliferation. Indeed, GPR55 antagonism increases cell proliferation and function determination in quasiphysiological systems. In addition, Gpr55-/- mice present ~50% enlarged submandibular glands with many more granulated ducts, as well as disordered endoplasmic reticuli and with glycoprotein content. Next, we hypothesized that GPR55 could also modulate salivation and glycoprotein content by entraining differentiated excretory progeny. Accordingly, GPR55 activation facilitated glycoprotein release by itself, inducing low-amplitude Ca2+ oscillations, as well as enhancing acetylcholine-induced Ca2+ responses. Topical application of GPR55 agonists, which are ineffective in Gpr55-/- mice, into adult rodent submandibular glands increased salivation and saliva glycoprotein content. Overall, we propose that GPR55 signaling in epithelial cells ensures both the life-long renewal of ductal cells and the continuous availability of saliva and glycoproteins for oral health and food intake.


Age-dependent regulation of excitatory synaptic transmission at hippocampal temporoammonic-CA1 synapses by leptin

May 2018

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592 Reads

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21 Citations

Neurobiology of Aging

The hippocampus is a key target for the hormone leptin and leptin regulation of excitatory synaptic transmission at Schaffer-collateral-CA1 synapses during aging are well documented. However, little is known about the age-dependent actions of leptin at the temporoammonic (TA) input to CA1 neurons. Here we show that leptin induces a novel form of N-methyl-D-aspartate receptor-dependent long-term depression (LTD) at adult (12-24 weeks old) TA-CA1 synapses. Leptin-induced LTD requires activation of canonical Janus tyrosine kinase 2- signal transducer and activator of transcription signaling and removal of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors from synapses. Moreover, leptin-induced LTD is occluded by activity-dependent LTD at TA-CA1 synapses. By contrast, leptin has no effect on excitatory synaptic transmission at aged (12-14 months old) TA-CA1 synapses, and low-frequency stimulation also fails to induce LTD at this age. These findings demonstrate clear age-related alterations in the leptin sensitivity of TA-CA1 synapses and provide valuable information on how the leptin system alters with age. As leptin has been linked to Alzheimer's disease, these findings have important implications for understanding of age-related disorders such as Alzheimer's disease.


Supplementary Material

August 2017

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91 Reads

Figure S1 Biological conformations of the arachidonic acid chain. (A, B) “C” type conformations of the polyene chain from diverse biological targets from X‐ray. This suggested that conformational restriction of (C) anandamide would be useful approach to generate novel molecules as in (D) VSN16. This has structural similarities with (E) N‐arachidonoyl glycine and (F) N‐arachidonoyl serine. Figure S2 VSN16R does not inhibit β γ methylene adenosine triphosphatase‐induced muscle contraction in the vas deferens. Mouse vas deferens were treated with either DMSO vehicle or 100 nM VSN16R 30 min before the first organ bath injection of various concentrations of βγ‐methylene ATP into the organ bath . The results represent the mean ± SEM of βγ‐methylene ATP‐induced increases in tension (expressed in grams) of electrically unstimulated vasa deferentia. (n = 6/group). Figure S3 Anaesthetics inhibit spasticity and muscle tone and can interfere with the action of VSN16R. (A) Strain gauge recording before and after (5 min) the induction of ketamine and medetomide anaesthesia, typically used for rodent electrophysiology studies. (B) Loss of muscle tone of spastic animals following anaesthetic showing measurement of resistance to limb flexion before and 5 min after anaesthesia.*** significant compared to baseline before anaesthetic using paired t‐test (n = 5 animals) (C) The magnitude of the H‐wave was measured in the shin muscle in spastic animals following sciatic nerve stimulation (100% = H wave at administration of 30 mg/kg i.v. VSN16R in PBS at 0 min). Although n = 0/3 PBS‐treated animals showed an inhibition of the H reflex, this could be inhibited by VSN16R (D) Electrophysiological trace of the shin muscle following stimulation of a spastic mouse before and after 30 mg/kg i.v. VSN16R administration. (E) However, the H reflex was only inhibited in some (3/5) animals responded (Green circles), whereas others did not (blue circles). Trace of individual mice (F) However, it was subsequently found that ketamine (200 μM. To represent anaesthetic levels in blood) can inhibit the mechanism of action of VSN16R in part of the dose–response curve to methoxamine‐evoked contraction of rat mesenteric artery (n = 5–6 cultures). Ketamine blocks NMDA receptors, that limits calcium ion fluxes that can influence BKCa function and can inhibit the inside‐out current of BKCa channels with an EC50 = ~25 μM (Denson DD et al. Brain Res 638:61). In contrast to healthy animals, mice with spasticity did not tolerate anaesthetics, which caused death in some instances, prompting discontinuation of the approach prior to attempted dose reduction. Figure S4 Patch Clamp analysis of VSN16R activity on BK Ca channels. (A) Primary pig aorta do not respond to VSN16R (n = 3 patches). Time course of the current development at −100 mV (lower) and +85 mV (upper) in response to VSN16R or the removal of potassium. (B) Whole cell currents of human EA.hy926 cells in response to voltage ramps before (control), and during exposure to 15 μM VSN16R in the absence and presence of 2 μM paxilline. The current represents the influence of endogenously expressed conducting ion channels within the cell, but the sensitivity to paxilline indicates that the majority response was mediated by BKca channels. (C‐E) This was shown in single channel patch clamp experiments in EA.hy926 cells. (C) Voltage dependence of activity of VSN16R in inside‐out patch clamp of single BKCa channels VSN16R. (D) Calcium dependence of activity of VSN16R. Single BKCa channel activity in inside‐out patch held at +60 mV and exposed to either 1 μM or 0.3 μM free Ca2+ concentrations before (control) and after treatment with 3 μM VSN16R. (E) VSN16R exhibits a concentration‐dependent induction of potassium currents in inside‐out patch clamp of single BKCa in EA.hy926 cells. The patch was held at 20 mV and exposed to 0.3 μM free Ca2+ under symmetrical K+ conditions. Representative traces that were repeated. Figure S5 Receptors and other targets that VSN16R fails to bind/activate (A) Receptors lacking activity with 10 μM VSN16R. Binding assays and positive controls were performed by Cerep, Multispan, DiscoverX, MDS pharma and Chantest. (B) Lack of activity of VSN16R on CB1 and CB2 cannabinoid receptors (C) Relative lack of activity of VSN16R agonism on U20S cells transfected with human GPR119 compared with oleoylethanolamide as assessed using cyclic AMP assay (D). HEK293 cells do not respond to lysophosphoinositol (LPI. GPR55 agonist) stimulation, but respond to lysophophatidic acid (LPA), unless they are transfected with human GPR55 (left) as assessed using calcium ion fluxes (Henstridge CM et al. Br J Pharmacol 2010; 160:604). (E) HEK293.GPR55 demonstrate calcium fluxes following stimulation with AM251 but do not respond to VSN16R (F) Lack of activity of VSN16R on DBT cells stably transfected with mouse Gpr55. These were incubated with 1‐3 μM LPI, 10 μM VSN16A or the 10 μM and the nuclear expression of cAMP response element‐binding protein (CREB) was assessed by immunocytochemistry (Henstridge et al. 2010). Table S1 VSN16R does not induce neurobehavioural behavioural tests in an Irwin test. Table S2 VSN16R does not induce cytochrome P450 enzymes. Table S3 VSN16R does not induce chromosomal mutagenesis. Table S4 VSN16R does not induce tissue toxicology of VSN16R in rats and dogs. Table S5 Lack of hypotension induced by VSN16R in dogs. Table S6 Demographics of humans in phase I double‐blind, placebo‐controlled trial. Table S7 Single Dose of VSN16R did not affect haematology and blood chemistry in humans. Table S8 Single dose of VSN16R did not affect coagulation, urinanalysis, vital signs and electrocardiograms in humans. Table S9 Lack of hypotension induced by VSN16R in humans.



Big conductance calcium-activated potassium channel openers control spasticity without sedation: BK Ca channels control spasticity

July 2017

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195 Reads

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24 Citations

Background & purpose: The initial aim was to generate cannabinoid agents that control spasticity, occurring as a consequence of multiple sclerosis, whilst avoiding the sedative, side-effect-potential associated with cannabis. (R,Z)-3-(6-(dimethylamino)-6-oxohex-1-enyl)-N-(1-hydroxypropan-2-yl)benzamide (VSN16R) was synthesized as an anandamide (endocannabinoid) analogue in an anti-metabolite approach to identify drug-like agents to target spasticity. Experimental approach: Following the initial chemistry, a variety of biochemical, pharmacological and electrophysiological approaches, using isolated cells, tissue-based assays and in vivo animal models, were used to demonstrate: activity, efficacy, pharmacokinetics and mechanism of action of the molecule. Toxicological and safety studies in animals and humans demonstrated tolerability of the molecule. Key results: VSN16R had nanomolar activity in tissue-based, functional assays and dose-dependently inhibited spasticity in a mouse experimental encephalomyelitis model of multiple sclerosis. This occurred with over a thousand-fold therapeutic window, without affecting normal muscle tone. Efficacy was achieved at plasma levels that were easily achievable and safe in humans. Interestingly, VSN16R did not bind to known CB1/CB2/GPPR55 cannabinoid-related receptors in receptor-based assays, but was found to act on a vascular cannabinoid target. This was identified to be the major neuronal form of the big conductance, calcium-activated potassium (BKCa ) channel. Drug-induced opening of neuronal BKCa channels induced membrane hyperpolarization to limit excessive neural-excitability and control spasticity. Conclusions and implications: This study identifies a novel role of BKCa channels, a novel mechanism to control spasticity and identifies a new, safe and selective type of ligand to control neural hyper-excitability in spasticity and a number of other neurological conditions.


Citations (79)


... By interacting with these areas, adipokines help sustain the cognitive control and emotional regulation necessary for executive function. Leptin, a hormone central to energy regulation, is shown to modulate hippocampal synaptic plasticity and memory processes (Irving & Harvey, 2021). Exercise enhances leptin sensitivity, amplifying its ability to influence neural circuits linked to decision-making and inhibitory control, two core functions of the CEN (Fedewa et al., 2018;Rodrigues et al., 2018;Valladolid-Acebes, 2024). ...

Reference:

Improving brain health via the central executive network
Regulation of hippocampal synaptic function by the metabolic hormone leptin: Implications for health and disease
  • Citing Article
  • April 2021

Progress in Lipid Research

... NAGlys, including CMD, belong to N-acyl amides [65,66], like some of the known endogenous agonists of GPCRs, e.g. palmitoyl and oleoylethanolamide (PEA and OEA, respectively), known as ligands of GPR55 and GPR119 [67]. ...

N-Palmitoylglycine and other N-acylamides activate the lipid receptor G2A/GPR132

... While no others receptors have yet been classified as a third cannabinoid receptor (Abood et al., 2019), there are a number of orphan and recently deorphanized G-protein coupled receptors which have been postulated as novel cannabinoid receptors in recent studies (Alexander and Irving, 2019;Kihara et al., 2014). These receptors may also contribute to the behavioural effects of cannabinoids on fear and anxiety, and could transform our understanding of the endocannabinoid system. ...

GPR18, GPR55 and GPR119 (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

IUPHAR/BPS Guide to Pharmacology CITE

... Thus, in juvenile slices, exposure to leptin results in a novel form of chemical LTP at TA-CA1 synapses [26], which is contrary to the depressant effects of leptin observed at juvenile SC-CA1 synapses. Similarly, the synaptic effects of leptin at adult TA-CA1 synapses completely oppose those reported at SC-CA1 synapses, as treatment with leptin leads to induction of LTD in adult TA-CA1 synapses [28]. Although leptin has divergent effects on the dual synaptic inputs onto CA1 pyramidal neurons, there are some similarities in the cellular processes involved in the different forms of synaptic plasticity induced by leptin. ...

Age-dependent regulation of excitatory synaptic transmission at hippocampal temporoammonic-CA1 synapses by leptin

Neurobiology of Aging

... Concluindo, o VSN16R emerge como um candidato promissor para o desenvolvimento de novos fármacos, pois não se liga aos receptores canabinóides CB1 ou CB2, evitando os efeitos psicoativos associados à cannabis. Com ensaios clínicos em andamento para avaliar sua eficácia no tratamento da espasticidade em pacientes com EM, o VSN16R representa uma perspectiva promissora no preenchimento de lacunas significativas no tratamento de condições neurológicas, oferecendo benefícios terapêuticos sem efeitos adversos indesejados(BAKER et al., 2017). Em adição ao exposto acima, é importante que também haja a discussão acerca da necessidade de se justificar financeiramente o uso da terapia com cannabis medicinal frente aos tratamentos já existentes, principalmente antes de introduzir tal opção terapêutica no sistema de saúde. ...

Big conductance calcium-activated potassium channel openers control spasticity without sedation: BK Ca channels control spasticity
  • Citing Article
  • July 2017

... Alternative lipid-sensing GPCR model An alternative explanation for the diversity of LPI responses may reside in the possible involvement of other receptors besides GPR55 which could mediate anti-in ammatory outcomes. For example, two other lipid-sensing (L-S) GPCR receptors have been associated with cannabinoids and both have reported effects on anti-in ammatory actions: GPR18 and GPR119 (Irving et al., 2017). These alternative GPCRs now have been brie y evaluated by three criteria relevant to the current studies: 1) the known tissue distribution of these (L-S) receptors; 2) the current evidence that these receptors produce an antiin ammatory action; and 3) reported responses of these receptors to LPI treatment. ...

Cannabinoid Receptor-Related Orphan G Protein-Coupled Receptors
  • Citing Chapter
  • June 2017

Advances in pharmacology (San Diego, Calif.)

... The leptin resistance characteristic of obesity impairs the activation of these two pathways, contributing to cognitive decline. 116,117 Also, leptin activity is directly associated with the prevention of Alzheimer's disease since leptin shows anti-amyloidogenic properties. On the one hand, leptin inhibits the catabolism of the APP and therefore the β-amyloid formation by inactivating the β-secretase enzyme. ...

Canonical JAK-STAT signaling is pivotal for long-term depression at adult hippocampal temporoammonic-CA1 synapses
  • Citing Article
  • May 2017

The FASEB Journal

... In the rat visual cortex in vitro we studied primarily potentiation of the NMDA response. Similar potentiations of the NMDA response have been seen in hippocampus ( Fitzjohn et al. 1996), striatum ( Pisani et al. 1997), spinal cord ( Jones and Headley 1995;Ugolini et al. 1999), and subthalamic nucleus ( Awad et al. 2000) with evidence that it is due to group I metabotropic glutamate receptors. However, a study of mouse cultured cortical neurons showed an inhibition of the NMDA response by DHPG ( Yu et al. 1997). ...

Erratum: Activation of grop I mGluRs potentiates NMDA responses in rat hippocampal slices' (Neuroscience Letters 203 (1996) (211-213))
  • Citing Article
  • January 1996

Neuroscience Letters

... The actin and microtubule dynamics, BDNF, nerve growth factor (NGF), neurotrophin (NT-3), neuron-glia cell adhesion molecules, drug abuse, and environmental chemical exposure affect axonal or dendritic growth, guidance, and branching [119][120][121][122]. E2 and ER effects on neuronal differentiation, axogenesis, and dendritogenesis have been widely reported. E2 regulates axonal and neuronal growth through various signaling pathways through highly expressed ER and GPER1 [123][124][125]. Although the cellular and molecular mechanisms that guide neuronal differentiation and morphogenesis have not yet been fully known, extensive studies over the past decade have begun to shed light on the molecular mechanisms that orchestrate growth, arborization, and dendrite and axon guidance. ...

Emerging roles for the novel estrogen-sensing receptor GPER1 in the CNS
  • Citing Article
  • July 2016

Neuropharmacology