Nk3R blockade has sex-divergent effects on memory in mice.

Background: Memory consolidation is a process required for the formation of long-term memories. The G-protein-coupled receptor (GPCR) neurokinin-3-receptor (Nk3R) and its interactions with sex hormones seem important for the modulation of fear memory consolidation: Nk3R antagonism in male mice impairs fear memory, but enhances it in females. However, the involvement of the Nk3R as a modulator of other memories in both sexes remains unexplored.

Functional Fine-Tuning of Metabolic Pathways by the Endocannabinoid System-Implications for Health and Disease.

The endocannabinoid system (ECS) employs a huge network of molecules (receptors, ligands, and enzymatic machinery molecules) whose interactions with other cellular networks have still not been fully elucidated. Endogenous cannabinoids are molecules with the primary function of control of multiple metabolic pathways. Maintenance of tissue and cellular homeostasis by functional fine-tuning of essential metabolic pathways is one of the key characteristics of the ECS.

The Interplay between Cancer Biology and the Endocannabinoid System-Significance for Cancer Risk, Prognosis and Response to Treatment.

The various components of the endocannabinoid system (ECS), such as the cannabinoid receptors (CBRs), cannabinoid ligands, and the signalling network behind it, are implicated in several tumour-related states, both as favourable and unfavourable factors. This review analyses the ECS's complex involvement in the susceptibility to cancer, prognosis, and response to treatment, focusing on its relationship with cancer biology in selected solid cancers (breast, gastrointestinal, gynaecological, prostate cancer, thoracic, thyroid, CNS tumours, and melanoma). Changes in the expression and activation of CBRs, as well as their ability to form distinct functional heteromers affect the cell's tumourigenic potential and their signalling properties, leading to pharmacologically different outcomes.

Modulation of dopamine D receptors via histamine H receptors is a novel therapeutic target for Huntington's disease.

Early Huntington's disease (HD) include over-activation of dopamine D receptors (DR), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce DR over-activation, we present a strategy based on targeting complexes of DR and histamine H receptors (HR). Using an HD mouse striatal cell model and HD mouse organotypic brain slices we found that DR-induced cell death signaling and neuronal degeneration, are mitigated by an HR antagonist.

Altered Signaling in CB1R-5-HT2AR Heteromers in Olfactory Neuroepithelium Cells of Schizophrenia Patients is Modulated by Cannabis Use.

Schizophrenia (SCZ) has been associated with serotonergic and endocannabinoid systems dysregulation, but difficulty in obtaining in vivo neurological tissue has limited its exploration. We investigated CB1R-5-HT2AR heteromer expression and functionality via intracellular pERK and cAMP quantification in olfactory neuroepithelium (ON) cells of SCZ patients non-cannabis users (SCZ/nc), and evaluated whether cannabis modulated these parameters in patients using cannabis (SCZ/c). Results were compared vs healthy controls non-cannabis users (HC/nc) and healthy controls cannabis users (HC/c).

The Kinetic Component in Drug Discovery: Using the Most Basic Pharmacological Concepts to Advance in Selecting Drugs to Combat CNS Diseases.

To reach the central nervous system (CNS), drugs must cross the brain-blood barrier and have appropriate pharmacokinetic/dynamic properties. However, in early drug discovery steps, the selection of lead compounds, for example, those targeting G-protein-coupled receptors (GPCRs), is made according to i) affinity, which is calculated in in vitro equilibrium conditions, and ii) potency, a signal transduction-related parameter, usually quantified at a fixed time-point in a heterologous expression system. This paper argues that kinetics must be considered in the early steps of lead compound selection.

Potentiation of cannabinoid signaling in microglia by adenosine A receptor antagonists.

Neuroprotective M2-skewed microglia appear as promising to alter the course of neurodegenerative diseases and G protein-coupled receptors (GPCRs) are potential targets to achieve such microglial polarization. A common feature of adenosine A (A R) and cannabinoid CB (CB R) GPCRs in microglia is that their expression is upregulated in Alzheimer's disease (AD). On the one hand, CB R seems a target for neuroprotection, delaying neurodegenerative processes like those associated to AD or Parkinson's diseases.

The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet?

The endocannabinoid system (ECS) has been placed in the anti-cancer spotlight in the last decade. The immense data load published on its dual role in both tumorigenesis and inhibition of tumor growth and metastatic spread has transformed the cannabinoid receptors CB1 (CB1R) and CB2 (CB2R), and other members of the endocannabinoid-like system, into attractive new targets for the treatment of various cancer subtypes. Although the clinical use of cannabinoids has been extensively documented in the palliative setting, clinical trials on their application as anti-cancer drugs are still ongoing.

Biased G Protein-Independent Signaling of Dopamine D-D Receptor Heteromers in the Nucleus Accumbens.

Several studies found in vitro evidence for heteromerization of dopamine D receptors (D1R) and D receptors (D3R), and it has been postulated that functional D1R-D3R heteromers that are normally present in the ventral striatum mediate synergistic locomotor-activating effects of D1R and D3R agonists in rodents. Based also on results obtained in vitro, with mammalian transfected cells, it has been hypothesized that those behavioral effects depend on a D1R-D3R heteromer-mediated G protein-independent signaling. Here, we demonstrate the presence on D1R-D3R heteromers in the mouse ventral striatum by using a synthetic peptide that selectively destabilizes D1R-D3R heteromers.

Therapeutic targeting of HER2-CBR heteromers in HER2-positive breast cancer.

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New therapeutic approaches and diagnostic tools for identification, stratification, and treatment of patients at higher risk of resistance and recurrence are therefore warranted. Here, we unveil a mechanism controlling the oncogenic activity of HER2: heteromerization with the cannabinoid receptor CBR.

Reinterpreting anomalous competitive binding experiments within G protein-coupled receptor homodimers using a dimer receptor model.

An increasing number of G protein-coupled receptors (GPCRs) have been reported to be expressed in the plasma membrane as dimers. Since most ligand binding data are currently fitted by classical equations developed only for monomeric receptors, the interpretation of data could be misleading in the presence of GPCR dimers. On the other hand, the equations developed from dimer receptor models assuming the existence of two orthosteric binding sites within the dimeric molecule offer the possibility to directly calculate macroscopic equilibrium dissociation constants for the two sites, an index of cooperativity (D) that reflects the molecular communication within the dimer and, importantly, a constant of radioligand-competitor allosteric interaction (K) in competitive assays.

Differential effect of amphetamine over the corticotropin-releasing factor CRF receptor, the orexin OX receptor and the CRF-OX heteroreceptor complex.

Stress is one of the factors underlying drug seeking behavior that often goes in parallel with loss of appetite. We here demonstrate that orexin 1 receptors (OXR) may form complexes with the corticotropin releasing factor CRF receptor. Two specific features of the heteromer were a cross-antagonism and a blockade by CRF of OXR signaling.

-Methyl-D-Aspartate Receptor Link to the MAP Kinase Pathway in Cortical and Hippocampal Neurons and Microglia Is Dependent on Calcium Sensors and Is Blocked by α-Synuclein, Tau, and Phospho-Tau in Non-transgenic and Transgenic APP Mice.

-methyl-D-aspartate receptors (NMDARs) respond to glutamate to allow the influx of calcium ions and the signaling to the mitogen-activated protein kinase (MAPK) cascade. Both MAPK- and Ca-mediated events are important for both neurotransmission and neural cell function and fate. Using a heterologous expression system, we demonstrate that NMDAR may interact with the EF-hand calcium-binding proteins calmodulin, calneuron-1, and NCS1 but not with caldendrin.

Cannabigerol Action at Cannabinoid CB and CB Receptors and at CB-CB Heteroreceptor Complexes.

Cannabigerol (CBG) is one of the major phytocannabinoids present in L. that is attracting pharmacological interest because it is non-psychotropic and is abundant in some industrial hemp varieties. The aim of this work was to investigate in parallel the binding properties of CBG to cannabinoid CB (CBR) and CB (CBR) receptors and the effects of the compound on agonist activation of those receptors and of CB-CB heteroreceptor complexes.

Cocaine Blocks Effects of Hunger Hormone, Ghrelin, Via Interaction with Neuronal Sigma-1 Receptors.

Despite ancient knowledge on cocaine appetite-suppressant action, the molecular basis of such fact remains unknown. Addiction/eating disorders (e.g.

Molecular and functional interaction between GPR18 and cannabinoid CB G-protein-coupled receptors. Relevance in neurodegenerative diseases.

GPR18, still considered an orphan receptor, may respond to endocannabinoids, whose canonical receptors are CB and CB. GPR18 and CB receptors share a role in peripheral immune response regulation and are co-expressed in microglia, which are immunocompetent cells in the central nervous system (CNS). We aimed at identifying heteroreceptor complexes formed by GPR18 and CBR or CBR in resting and activated microglia.

Adenosine A-Dopamine D Receptor Heteromers Control the Excitability of the Spinal Motoneuron.

While the role of the ascending dopaminergic system in brain function and dysfunction has been a subject of extensive research, the role of the descending dopaminergic system in spinal cord function and dysfunction is just beginning to be understood. Adenosine plays a key role in the inhibitory control of the ascending dopaminergic system, largely dependent on functional complexes of specific subtypes of adenosine and dopamine receptors. Combining a selective destabilizing peptide strategy with a proximity ligation assay and patch-clamp electrophysiology in slices from male mouse lumbar spinal cord, the present study demonstrates the existence of adenosine A-dopamine D receptor heteromers in the spinal motoneuron by which adenosine tonically inhibits D receptor-mediated signaling.

Evidence for functional pre-coupled complexes of receptor heteromers and adenylyl cyclase.

G protein-coupled receptors (GPCRs), G proteins and adenylyl cyclase (AC) comprise one of the most studied transmembrane cell signaling pathways. However, it is unknown whether the ligand-dependent interactions between these signaling molecules are based on random collisions or the rearrangement of pre-coupled elements in a macromolecular complex. Furthermore, it remains controversial whether a GPCR homodimer coupled to a single heterotrimeric G protein constitutes a common functional unit.

α- and α-Adrenoceptors as Potential Targets for Dopamine and Dopamine Receptor Ligands.

The poor norepinephrine innervation and high density of Gi/o-coupled α- and α-adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D-like receptor ligands, such as the D receptor agonist 7-OH-PIPAT and the D receptor agonist RO-105824, to α-adrenoceptors in cortical and striatal tissue, which express α-adrenoceptors and both α- and α-adrenoceptors, respectively.