scholarly journals Nanoscale Sub-Compartmentalization of the Dendritic Spine Compartment

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1697
Author(s):  
Ana Sofía Vallés ◽  
Francisco J. Barrantes
Keyword(s):  
Dendritic Spine ◽  
Cannabinoid Receptor ◽  
Postsynaptic Membrane ◽  
Cell Physiology ◽  
Excitatory Synapses ◽  
Scaffolding Proteins ◽  
Signaling Systems ◽  
Functional Relevance ◽  
G Protein Coupled ◽  
Lateral Heterogeneities

Compartmentalization of the membrane is essential for cells to perform highly specific tasks and spatially constrained biochemical functions in topographically defined areas. These membrane lateral heterogeneities range from nanoscopic dimensions, often involving only a few molecular constituents, to micron-sized mesoscopic domains resulting from the coalescence of nanodomains. Short-lived domains lasting for a few milliseconds coexist with more stable platforms lasting from minutes to days. This panoply of lateral domains subserves the great variety of demands of cell physiology, particularly high for those implicated in signaling. The dendritic spine, a subcellular structure of neurons at the receiving (postsynaptic) end of central nervous system excitatory synapses, exploits this compartmentalization principle. In its most frequent adult morphology, the mushroom-shaped spine harbors neurotransmitter receptors, enzymes, and scaffolding proteins tightly packed in a volume of a few femtoliters. In addition to constituting a mesoscopic lateral heterogeneity of the dendritic arborization, the dendritic spine postsynaptic membrane is further compartmentalized into spatially delimited nanodomains that execute separate functions in the synapse. This review discusses the functional relevance of compartmentalization and nanodomain organization in synaptic transmission and plasticity and exemplifies the importance of this parcelization in various neurotransmitter signaling systems operating at dendritic spines, using two fast ligand-gated ionotropic receptors, the nicotinic acetylcholine receptor and the glutamatergic receptor, and a second-messenger G-protein coupled receptor, the cannabinoid receptor, as paradigmatic examples.

scholarly journals Minireview: Role of Intracellular Scaffolding Proteins in the Regulation of Endocrine G Protein-Coupled Receptor Signaling

2015 ◽  
Vol 29 (6) ◽  
pp. 814-830 ◽  
Author(s):  
Cornelia Walther ◽  
Stephen S. G. Ferguson
Keyword(s):  
Signaling Pathways ◽  
G Protein ◽  
Potential Role ◽  
Cell Physiology ◽  
Scaffolding Proteins ◽  
Receptor Signaling ◽  
Heterotrimeric G Proteins ◽  
Zona Occludens ◽  
G Protein Coupled

Abstract The majority of hormones stimulates and mediates their signal transduction via G protein-coupled receptors (GPCRs). The signal is transmitted into the cell due to the association of the GPCRs with heterotrimeric G proteins, which in turn activates an extensive array of signaling pathways to regulate cell physiology. However, GPCRs also function as scaffolds for the recruitment of a variety of cytoplasmic protein-interacting proteins that bind to both the intracellular face and protein interaction motifs encoded by GPCRs. The structural scaffolding of these proteins allows GPCRs to recruit large functional complexes that serve to modulate both G protein-dependent and -independent cellular signaling pathways and modulate GPCR intracellular trafficking. This review focuses on GPCR interacting PSD95-disc large-zona occludens domain containing scaffolds in the regulation of endocrine receptor signaling as well as their potential role as therapeutic targets for the treatment of endocrinopathies.

Short-Term Potentiation of Miniature Excitatory Synaptic Currents Causes Excitation of Supraoptic Neurons

2000 ◽  
Vol 83 (5) ◽  
pp. 2542-2553 ◽  
Author(s):  
Samuel B. Kombian ◽  
Michiru Hirasawa ◽  
Didier Mouginot ◽  
Xihua Chen ◽  
Quentin J. Pittman
Keyword(s):  
Nmda Receptors ◽  
Postsynaptic Membrane ◽  
High Frequency Stimulation ◽  
Excitatory Synapses ◽  
Short Term ◽  
Cell Excitability ◽  
Term Potentiation ◽  
Before And After ◽  
Frequency Stimulation ◽  
Supraoptic Neurons

Magnocellular neurons (MCNs) of the hypothalamic supraoptic nucleus (SON) secrete vasopressin and oxytocin. With the use of whole-cell and nystatin-perforated patch recordings of MCNs in current- and voltage-clamp modes, we show that high-frequency stimulation (HFS, 10–200 Hz) of excitatory afferents induces increases in the frequency and amplitude of 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide (NBQX)-sensitive miniature excitatory postsynaptic currents (mEPSCs) lasting up to 20 min. This synaptic enhancement, referred to as short-term potentiation (STP), could be induced repeatedly; required tetrodotoxin (TTX)-dependent action potentials to initiate, but not to maintain; and was independent of postsynaptic membrane potential, N-methyl-d-aspartate (NMDA) receptors, or retrograde neurohypophyseal neuropeptide release. STP was not accompanied by changes in the conductance of the MCNs or in the responsiveness of the postsynaptic non-NMDA receptors, as revealed by brief application of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate. mEPSCs showed similar rise times before and after HFS and analysis of amplitude distributions of mEPSCs revealed one or more peaks pre-HFS and the appearance of additional peaks post-HFS, which were equidistant from the first peak. STP of mEPSCs was not associated with enhanced evoked responses, but was associated with an NBQX-sensitive increase in spontaneous activity of MCNs. Thus we have identified a particularly long-lasting potentiation of excitatory synapses in the SON, which has a presynaptic locus, is dissociated from changes in evoked release, and which regulates postsynaptic cell excitability.

scholarly journals G protein-coupled receptor GPR55 promotes colorectal cancer and has opposing effects to cannabinoid receptor 1

2017 ◽  
Vol 142 (1) ◽  
pp. 121-132 ◽  
Author(s):  
Carina Hasenoehrl ◽  
David Feuersinger ◽  
Eva M Sturm ◽  
Thomas Bärnthaler ◽  
Ellen Heitzer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
G Protein ◽  
Cannabinoid Receptor ◽  
G Protein Coupled Receptor ◽  
Cannabinoid Receptor 1 ◽  
Opposing Effects ◽  
G Protein Coupled

scholarly journals The Spicy Story of Cannabimimetic Indoles

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6190
Author(s):  
Allyn C. Howlett ◽  
Brian F. Thomas ◽  
John W. Huffman
Keyword(s):  
Electrostatic Interactions ◽  
Cannabinoid Receptor ◽  
Binding Pocket ◽  
Herbal Products ◽  
The Public ◽  
Aromatic Stacking ◽  
Cb1 Cannabinoid Receptor ◽  
Colchicine Binding Site ◽  
Consumer Safety ◽  
G Protein Coupled

The Sterling Research Group identified pravadoline as an aminoalkylindole (AAI) non-steroidal anti-inflammatory pain reliever. As drug design progressed, the ability of AAI analogs to block prostaglandin synthesis diminished, and antinociceptive activity was found to result from action at the CB1 cannabinoid receptor, a G-protein-coupled receptor (GPCR) abundant in the brain. Several laboratories applied computational chemistry methods to ultimately conclude that AAI and cannabinoid ligands could overlap within a common binding pocket but that WIN55212-2 primarily utilized steric interactions via aromatic stacking, whereas cannabinoid ligands required some electrostatic interactions, particularly involving the CB1 helix-3 lysine. The Huffman laboratory identified strategies to establish CB2 receptor selectivity among cannabimimetic indoles to avoid their CB1-related adverse effects, thereby stimulating preclinical studies to explore their use as anti-hyperalgesic and anti-allodynic pharmacotherapies. Some AAI analogs activate novel GPCRs referred to as “Alkyl Indole” receptors, and some AAI analogs act at the colchicine-binding site on microtubules. The AAI compounds having the greatest potency to interact with the CB1 receptor have found their way into the market as “Spice” or “K2”. The sale of these alleged “herbal products” evades FDA consumer protections for proper labeling and safety as a medicine, as well as DEA scheduling as compounds having no currently accepted medical use and a high potential for abuse. The distribution to the public of potent alkyl indole synthetic cannabimimetic chemicals without regard for consumer safety contrasts with the adherence to regulatory requirements for demonstration of safety that are routinely observed by ethical pharmaceutical companies that market medicines.

scholarly journals Interactions of the G protein-coupled receptor-associated sorting proteins (GASP) 1 and 2 with the novel cannabinoid receptor GPR55

2008 ◽  
Vol 8 (Suppl 1) ◽  
pp. A16
Author(s):  
Julia Kargl ◽  
Nariman Balenga ◽  
Lene Martini ◽  
Jennifer Whistler ◽  
Maria Waldhoer
Keyword(s):  
G Protein ◽  
Cannabinoid Receptor ◽  
The Novel ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals BDNF signaling during the lifetime of dendritic spines

2020 ◽  
Vol 382 (1) ◽  
pp. 185-199 ◽  
Author(s):  
Marta Zagrebelsky ◽  
Charlotte Tacke ◽  
Martin Korte
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Neurological Disorders ◽  
Current Knowledge ◽  
Conclusive Evidence ◽  
Excitatory Synapses ◽  
Neuronal Homeostasis ◽  
Bdnf Signaling ◽  
Spine Number

Abstract Dendritic spines are tiny membrane specialization forming the postsynaptic part of most excitatory synapses. They have been suggested to play a crucial role in regulating synaptic transmission during development and in adult learning processes. Changes in their number, size, and shape are correlated with processes of structural synaptic plasticity and learning and memory and also with neurodegenerative diseases, when spines are lost. Thus, their alterations can correlate with neuronal homeostasis, but also with dysfunction in several neurological disorders characterized by cognitive impairment. Therefore, it is important to understand how different stages in the life of a dendritic spine, including formation, maturation, and plasticity, are strictly regulated. In this context, brain-derived neurotrophic factor (BDNF), belonging to the NGF-neurotrophin family, is among the most intensively investigated molecule. This review would like to report the current knowledge regarding the role of BDNF in regulating dendritic spine number, structure, and plasticity concentrating especially on its signaling via its two often functionally antagonistic receptors, TrkB and p75NTR. In addition, we point out a series of open points in which, while the role of BDNF signaling is extremely likely conclusive, evidence is still missing.

scholarly journals Cannabinoids: A New Group of Agonists of PPARs

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-7 ◽  
Author(s):  
Yan Sun ◽  
Andy Bennett
Keyword(s):  
Cannabinoid Receptor ◽  
Peroxisome Proliferator ◽  
Cannabinoid Receptor 1 ◽  
Nuclear Receptor Superfamily ◽  
Psychotropic Effects ◽  
Inflammatory Drugs ◽  
Peroxisome Proliferator Activated Receptors ◽  
New Compounds ◽  
G Protein Coupled ◽  
Recreational Use

Cannabinoids have been used medicinally and recreationally for thousands of years and their effects were proposed to occur mainly via activation of the G-protein-coupled receptorCB1/CB2(cannabinoid receptor 1/2). Discovery of potent synthetic analogs of the natural cannabinoids as clinically useful drugs is the sustained aim of cannabinoid research. This demands that these new compounds be free of the psychotropic effects that connected with the recreational use of cannabinoids. In preclinical studies cannabinoids displayed many of the characteristics of nonsteroidal anti-inflammatory drugs (NSAIDs) and it seems to be free of unwanted side effects. An increasing number of therapeutic actions of cannabinoid are being reported that do not appear to be mediated by eitherCB1orCB2, and recently nuclear receptor superfamily PPARs (peroxisome-proliferator-activated receptors) have been suggested as the target of certain cannabinoids. This review summarizes the evidence for cannabinoid activation on PPARs and possible associated remedial potentials.

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