Presynaptic Inhibition of GABAA Receptor-Mediated Unitary IPSPs by Cannabinoid Receptors at Synapses Between CCK-Positive Interneurons in Rat Hippocampus

2007 ◽  
Vol 98 (2) ◽  
pp. 861-869 ◽  
Author(s):  
Afia B. Ali
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Electrical Coupling ◽  
Cb1 Receptor ◽  
Spike Timing ◽  
Rat Hippocampus ◽  
Stratum Radiatum ◽  
Synaptic Interactions ◽  
Immunofluorescence Labeling ◽  
Endogenous Cannabinoid

There is growing evidence to link cholecystokinin (CCK)-positive interneurons and anxiety disorders. Despite this, little is known about the physiology and pharmacology of synaptic interactions between CCK-positive interneurons. This study aims to investigate the local circuit connections among CCK-positive Schaffer collateral associated (SCA) interneurons in stratum radiatum (SR) and their modulatory interactions using paired whole cell recordings combined with biocytin and double immunofluorescence labeling in slices of rat hippocampus. The cell bodies of SCA interneurons were located in SR, and their sparsely spiny dendrites projected toward s. pyramidale (SP) and along SR. Their axons innervated SR, SP, and s. oriens (SO) with predominant ramification in SR. These cells were immunopositive for CCK and immunonegative for parvalbumin (PV). SCA interneurons often displayed an accommodating firing pattern with or without a “sag” in response to hyperpolarizing current injection. Pairs of these cells exhibited electrical coupling and reciprocal chemical connections in which inhibitory postsynaptic potentials (IPSPs) displayed powerful frequency-dependent facilitation and augmentation. The synaptic connections were modulated by the endogenous cannabinoid receptor (CB) agonist, anandamide and by depolarization-induced suppression of inhibition (DSI), both of which reduced the amplitude of unitary IPSPs to 50% of control and increased the number of apparent failures of transmission. These effects were blocked by the CB1 receptor antagonist, AM-251. I suggest that synaptic facilitation between CCK-positive SCA interneurons may modify the onset of CB1 receptor-mediated regulation of inhibition, thereby affecting spike timing, and that this process could influence the expression of anxiety.

Molecular Modeling of an Orphan GPR18 Receptor

2019 ◽  
Vol 16 (10) ◽  
pp. 1167-1174 ◽  
Author(s):  
Kamil J. Kuder ◽  
Tadeusz Karcz ◽  
Maria Kaleta ◽  
Katarzyna Kiec-Kononowicz
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Glycine Receptor ◽  
Homology Model ◽  
Orphan Receptor ◽  
Receptor Ligands ◽  
Orphan Receptors ◽  
Inactive Form ◽  
Starting Point ◽  
Endogenous Cannabinoid

Background: : One of the best known to date GPCR class A (Rhodopsin) includes more than 100 orphan receptors for which the endogenous ligand is not known or is unclear. One of them is N-arachidonyl glycine receptor, named GPR18, a receptor that has been reported to be activated by Δ9-THC, endogenous cannabinoid receptors agonist anandamide and other cannabinoid receptor ligands suggesting it could be considered as third cannabinoid receptor. GPR18 activity, as well as its distribution might suggest usage of GPR18 ligands in treatment of endometriosis, cancer, and neurodegenerative disorders. Yet, so far only few GPR18 antagonists have been described, thus only ligand-based design approaches appear to be most useful to identify new ligands for this orphan receptor. Methods: : Main goal of this study, GPR18 inactive form homology model was built on the basis of the evolutionary closest homologous template: Human P2Y1 Receptor crystal structure. Results: : Obtained model was further evaluated and showed active/nonactive ligands differentiating properties with acceptable confidence. Moreover, it allowed for preliminary assessment of proteinligand interactions for a set of previously described ligands. Conclusion:: Thus collected data might serve as a starting point for a discovery of novel, active GPR18 blocking ligands.

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

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Stephen P.H. Alexander ◽  
Andrew J. Irving
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Structural Similarity ◽  
Synthetic Cannabinoid ◽  
Receptor Ligands ◽  
Orphan Status ◽  
Endogenous Cannabinoid

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.

Cannabinoids Inhibit N- and P/Q-Type Calcium Channels in Cultured Rat Hippocampal Neurons

1997 ◽  
Vol 78 (1) ◽  
pp. 43-50 ◽  
Author(s):  
W. Twitchell ◽  
S. Brown ◽  
K. Mackie
Keyword(s):  
Calcium Channels ◽  
Hippocampal Neurons ◽  
Cannabinoid Receptor ◽  
Sympathetic Neurons ◽  
Cb1 Receptor ◽  
Cannabinoid Cb1 Receptor ◽  
Central Neurons ◽  
Cb1 Antagonist ◽  
Cp 55,940 ◽  
Endogenous Cannabinoid

Twitchell, W., S. Brown, and K. Mackie. Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons. J. Neurophysiol. 78: 43–50, 1997. Cannabinoids and their analogues have been found to inhibit N- and P/Q-type Ca2+ currents in cell lines and sympathetic neurons transfected with cannabinoid CB1 receptor. However, the effects of cannabinoids on Ca2+ currents in the CNS are largely unexplored. In this study we investigated whether these compounds inhibit Ca2+ channels in cultured rat hippocampal neurons. With the use of antibodies directed against the amino-terminus of the CB1 receptor, we found that in 5-day cultures pyramidally shaped neurons expressed somatic CB1 receptors, whereas in 4-wk cultures the receptor was predomintely located on neurites. In early cultures, the cannabimimetic WIN 55,212-2 reversibly inhibited whole cell Ba2+ current in a concentration-dependent ( K 1/2 = 21 nM) and pertussis-toxin-sensitive fashion. Inhibition was reduced by the CB1 antagonist SR141716. The current was unaffected by the nonpsychoactive enantiomer WIN 55,212-3. Maximal inhibition by the nonclassical cannabinoid agonist CP 55,940 and by an endogenous cannabinoid, anandamide, were similar to that seen with maximal concentrations of WIN 55,212-2. The Ba2+ current modulated by cannabinoids was carried by N-type (ω-conotoxin-GVIA-sensitive) and P/Q-type (ω-conotoxin-MVIIC-sensitive) channels. These results demonstrate cannabinoid-receptor-mediated inhibition of distinct Ca2+ channels in central neurons. Because the channels that underlie these currents are chiefly located presynaptically, and are required for evoked neurotransmitter release, our results suggest a major role for cannabinoids (endogenous and exogenous) in the modulation of synaptic transmission at CNS synapses.

scholarly journals CB1 modulation of temporally distinct synaptic facilitation among local circuit interneurons mediated by N-type calcium channels in CA1

2011 ◽  
Vol 105 (3) ◽  
pp. 1051-1062 ◽  
Author(s):  
Afia B. Ali
Keyword(s):  
Calcium Channels ◽  
Signal Transmission ◽  
Cb1 Receptor ◽  
Stratum Radiatum ◽  
Cb1 Receptors ◽  
Frequency Dependent ◽  
Local Circuit ◽  
Synaptic Facilitation ◽  
Presynaptic Calcium ◽  
Immunofluorescence Labeling

One of the critical factors in determining network behavior of neurons is the influence of local circuit connections among interneurons. The short-term synaptic plasticity and the subtype of presynaptic calcium channels used at local circuit connections of inhibitory interneurons in CA1 were investigated using dual whole-cell recordings combined with biocytin and double immunofluorescence labeling in acute slices of P18- to 21-day-old rat stratum radiatum (SR) and stratum lacunosum moleculare (SLM). Two forms of temporally distinct synaptic facilitation were observed among interneuron connections involving presynaptic cholecystokinin (CCK)-positive cells in SR, frequency-dependent facilitation, and a delayed onset of release (45–80 ms) with subsequent facilitation (DORF). Inhibition at both these synapses was under tonic cannabinoid-type 1 (CB1) receptor activity. DORF synapses did not display conventional release-dependent properties; however, blocking CB1 receptors with antagonist AM-251 (10 μM) altered the synaptic transmission to frequency-dependent depression with a fast onset of release (2–4 ms). Presynaptic CCK-negative interneurons in SLM elicited inhibitory postsynaptic potentials (IPSPs) insensitive to CB1 receptor pharmacology displayed frequency-dependent depression. Release of GABA at facilitating synapses was solely mediated via N-type presynaptic calcium channels, whereas depressing synapses utilized P/Q-type channels. These data reveal two distinct models of neurotransmitter release patterns among interneuron circuits that correlate with the subtype of presynaptic calcium channel. These data suggest that endocannabinoids act via CB1 receptors to selectively modulate N-type calcium channels to alter signal transmission.

scholarly journals The Role of Cannabinoids in Bone Metabolism: A New Perspective for Bone Disorders

2021 ◽  
Vol 22 (22) ◽  
pp. 12374
Author(s):  
Federica Saponaro ◽  
Rebecca Ferrisi ◽  
Francesca Gado ◽  
Beatrice Polini ◽  
Alessandro Saba ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Bone Cells ◽  
Local Level ◽  
Bone Diseases ◽  
Skeletal Health ◽  
Messenger Molecules ◽  
New Perspective ◽  
Endogenous Cannabinoid

Novel interest has arisen in recent years regarding bone, which is a very complex and dynamic tissue deputed to several functions ranging from mechanical and protective support to hematopoiesis and calcium homeostasis maintenance. In order to address these tasks, a very refined, continuous remodeling process needs to occur involving the coordinated action of different types of bone cells: osteoblasts (OBs), which have the capacity to produce newly formed bone, and osteoclasts (OCs), which can remove old bone. Bone remodeling is a highly regulated process that requires many hormones and messenger molecules, both at the systemic and the local level. The whole picture is still not fully understood, and the role of novel actors, such as the components of the endocannabinoids system (ECS), including endogenous cannabinoid ligands (ECs), cannabinoid receptors (CBRs), and the enzymes responsible for endogenous ligand synthesis and breakdown, is extremely intriguing. This article reviews the connection between the ECS and skeletal health, supporting the potential use of cannabinoid receptor ligands for the treatment of bone diseases associated with accelerated osteoclastic bone resorption, including osteoporosis and bone metastasis.

The cloning and characterization of the cannabinoid type 1 receptor

2018 ◽  
Author(s):  
Mary E. Abood ◽  
Thomas Gamage
Keyword(s):  
Chronic Pain ◽  
Cannabinoid Receptor ◽  
Functional Characterization ◽  
Endocannabinoid System ◽  
Cb1 Receptor ◽  
Cannabinoid Type 1 Receptor ◽  
Endogenous Cannabinoid ◽  
Endogenous Cannabinoid System

The cloning and characterization of the first cannabinoid receptor (now known as the cannabinoid type 1 (CB1) receptor) by Matsuda et al. in the landmark paper discussed in this chapter was a seminal discovery in 1990. While the analgesic properties of marijuana had been known for thousands of years, the mechanisms through which marijuana produces analgesia were not understood. The identification and functional characterization of the CB1 receptor led to the discovery of an endogenous cannabinoid system (the endocannabinoid system), which has now been shown to be important not only for acute and chronic pain states, but also for a whole host of physiological and pathophysiological disorders.

Cannabinoid Receptor Modulation of Synapses Received by Cerebellar Purkinje Cells

2000 ◽  
Vol 83 (3) ◽  
pp. 1167-1180 ◽  
Author(s):  
Kanji A. Takahashi ◽  
David J. Linden
Keyword(s):  
Neurotransmitter Release ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Receptor Activation ◽  
Cb1 Receptor ◽  
Vesicle Release ◽  
Voltage Gated ◽  
Postsynaptic Currents ◽  
Voltage Gated Channels ◽  
Release Processes

The high density of cannabinoid receptors in the cerebellum and the degradation of motor coordination produced by cannabinoid intoxication suggest that synaptic transmission in the cerebellum may be strongly regulated by cannabinoid receptors. Therefore the effects of exogenous cannabinoids on synapses received by Purkinje cells were investigated in rat cerebellar slices. Parallel fiber–evoked (PF) excitatory postsynaptic currents (EPSCs) were strongly inhibited by bath application of the cannabinoid receptor agonist WIN 55212-2 (5 μM, 12% of baseline EPSC amplitude). This effect was completely blocked by the cannabinoid CB1 receptor antagonist SR 141716. It is unlikely that this was the result of alterations in axonal excitability because fiber volley velocity and kinetics were unchanged and a cannabinoid-induced decrease in fiber volley amplitude was very minor (93% of baseline). WIN 55212-2 had no effect on the amplitude or frequency of spontaneously occurring miniature EPSCs (mEPSCs), suggesting that the effect of CB1 receptor activation on PF EPSCs was presynaptically expressed, but giving no evidence for modulation of release processes after Ca2+influx. EPSCs evoked by climbing fiber (CF) stimulation were less powerfully attenuated by WIN 55212-2 (5 μM, 74% of baseline). Large, action potential–dependent, spontaneously occurring inhibitory postsynaptic currents (sIPSCs) were either severely reduced in amplitude (<25% of baseline) or eliminated. Miniature IPSCs (mIPSCs) were reduced in frequency (52% of baseline) but not in amplitude, demonstrating suppression of presynaptic vesicle release processes after Ca2+ influx and suggesting an absence of postsynaptic modulation. The decrease in mIPSC frequency was not large enough to account for the decrease in sIPSC amplitude, suggesting that presynaptic voltage-gated channel modulation was also involved. Thus, while CB1 receptor activation reduced neurotransmitter release at all major classes of Purkinje cell synapses, this was not accomplished by a single molecular mechanism. At excitatory synapses, cannabinoid suppression of neurotransmitter release was mediated by modulation of voltage-gated channels in the presynaptic axon terminal. At inhibitory synapses, in addition to modulation of presynaptic voltage-gated channels, suppression of the downstream vesicle release machinery also played a large role.

scholarly journals Cannabinoid receptors distribution in mouse cortical plasma membrane compartments

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Hajar Miranzadeh Mahabadi ◽  
Haseeb Bhatti ◽  
Robert B. Laprairie ◽  
Changiz Taghibiglou
Keyword(s):  
Plasma Membrane ◽  
Lipid Raft ◽  
Cannabinoid Receptors ◽  
Gradient Centrifugation ◽  
Brain Regions ◽  
Cb1 Receptor ◽  
The Body ◽  
Cb2 Receptor ◽  
Cortical Tissue ◽  
Ionic Detergent

AbstractThe type 1 and type 2 cannabinoid receptors (CB1 and CB2 receptors) are class A G protein-coupled receptors (GPCRs) that are activated by endogenous lipids called endocannabinoids to modulate neuronal excitability and synaptic transmission in neurons throughout the central nervous system (CNS), and inflammatory processes throughout the body. CB1 receptor is one of the most abundant GPCRs in the CNS and is involved in many physiological and pathophysiological processes, including mood, appetite, and nociception. CB2 receptor is primarily found on immunomodulatory cells of both the CNS and the peripheral immune system. In this study, we isolated lipid raft and non-lipid raft fractions of plasma membrane (PM) from mouse cortical tissue by using cold non-ionic detergent and sucrose gradient centrifugation to study the localization of CB1 receptor and CB2 receptor. Lipid raft and non-lipid raft fractions were confirmed by flotillin-1, caveolin-1 and transferrin receptor as their protein biomarkers. Both CB1 receptor and CB2 receptor were found in non-raft compartments that is inconsistent with previous findings in cultured cell lines. This study demonstrates compartmentalization of both CB1 receptor and CB2 receptor in cortical tissue and warrants further investigation of CB1 receptor and CB2 receptor compartmental distribution in various brain regions and cell types.

scholarly journals Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain

2021 ◽  
Vol 22 (15) ◽  
pp. 8051
Author(s):  
Rodrigo Teodoro ◽  
Daniel Gündel ◽  
Winnie Deuther-Conrad ◽  
Lea Ueberham ◽  
Magali Toussaint ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Biological Evaluation ◽  
Emission Tomography ◽  
Tailored Therapy ◽  
Positron Emission ◽  
Cannabinoid Receptor Type 2 ◽  
Attractive Therapeutic Target ◽  
The Brain

Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis-[18F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([18F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [18F]LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression.

scholarly journals Therapeutic Attributes of Endocannabinoid System against Neuro-Inflammatory Autoimmune Disorders

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3389
Author(s):  
Ishtiaq Ahmed ◽  
Saif Ur Rehman ◽  
Shiva Shahmohamadnejad ◽  
Muhammad Anjum Zia ◽  
Muhammad Ahmad ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Therapeutic Potential ◽  
Endocannabinoid System ◽  
Cell Types ◽  
Autoimmune Disorders ◽  
Specific Receptors ◽  
Different Cell Types

In humans, various sites like cannabinoid receptors (CBR) having a binding affinity with cannabinoids are distributed on the surface of different cell types, where endocannabinoids (ECs) and derivatives of fatty acid can bind. The binding of these substance(s) triggers the activation of specific receptors required for various physiological functions, including pain sensation, memory, and appetite. The ECs and CBR perform multiple functions via the cannabinoid receptor 1 (CB1); cannabinoid receptor 2 (CB2), having a key effect in restraining neurotransmitters and the arrangement of cytokines. The role of cannabinoids in the immune system is illustrated because of their immunosuppressive characteristics. These characteristics include inhibition of leucocyte proliferation, T cells apoptosis, and induction of macrophages along with reduced pro-inflammatory cytokines secretion. The review seeks to discuss the functional relationship between the endocannabinoid system (ECS) and anti-tumor characteristics of cannabinoids in various cancers. The therapeutic potential of cannabinoids for cancer—both in vivo and in vitro clinical trials—has also been highlighted and reported to be effective in mice models in arthritis for the inflammation reduction, neuropathic pain, positive effect in multiple sclerosis and type-1 diabetes mellitus, and found beneficial for treating in various cancers. In human models, such studies are limited; thereby, further research is indispensable in this field to get a conclusive outcome. Therefore, in autoimmune disorders, therapeutic cannabinoids can serve as promising immunosuppressive and anti-fibrotic agents.

Sign in / Sign up

Export Citation Format

Share Document