Excessive Receptor Stimulation Research Articles

The effect of mutation on neurotoxicity reduction of new chimeric reteplase, a computational study.

Excitotoxicity in nerve cells is a type of neurotoxicity in which excessive stimulation of receptors (such as N-methyl-d-aspartate glutamate receptors (NMDAR)) leads to the influx of high-level calcium ions into cells and finally cell damage or death. This complication can occur after taking some of the plasminogen activators like tissue plasminogen activator and reteplase. The interaction of the kringle2 domain in such plasminogen activator with the amino-terminal domain (ATD) of the NR1 subunit of NMDAR finally leads to excitotoxicity. In this study, we assessed the interaction of two new chimeric reteplase, mutated in the kringle2 domain, with ATD and compared the interaction of wild-type reteplase with ATD, computationally. Homology modeling, protein docking, molecular dynamic simulation, and molecular dynamics trajectory analysis were used for the assessment of this interaction. The results of the free energy analysis between reteplase and ATD (wild reteplase: -2127.516 ± 0.0, M1-chr: -1761.510 ± 0.0, M2-chr: -521.908 ± 0.0) showed lower interaction of this chimeric reteplase with ATD compared to the wild type. The decreased interaction between two chimeric reteplase and ATD of NR1 subunit in NMDAR which leads to lower neurotoxicity related to these drugs, can be the start of a way to conduct more tests and if the results confirm this feature, they can be considered potential drugs in acute ischemic stroke treatment.

Autoantibodies directed against \u03b11-adrenergic receptor and endothelin receptor A in patients with prostate cancer

BackgroundFor prostate cancer, signaling pathways induced by over-boarding stimulation of G-protein coupled receptors (GPCR) such as the endothelin, α1- and β-adrenergic, muscarinic and angiotensin 1 receptors were accused to support the carcinogenesis. However, excessive receptor stimulation by physiological receptor ligands is minimized by a control system that induces receptor sensitization and down-regulation. This system is missing when so-called “functional autoantibodies” bind to the GPCR (GPCR-AAB). If GPCR-AAB were found in patients with prostate cancer, uncontrolled GPCR stimulation could make these autoantibodies an additional supporter in prostate cancer.MethodsUsing the bioassay of spontaneously beating cultured rat neonatal cardiomyocytes, GPCR-AAB were identified, quantified and characterized in the serum of 25 patients (aged 56–78 years, median 70 years) with prostate cancer compared to 10 male patients (aged 48–82 years, median 64) with urinary stone disorders (controls).ResultsOf the cancer patients, 24 (96%) and 17 (68%), respectively, carried autoantibodies directed against the α1-adrenergic receptor (α1-AAB) and endothelin receptor A (ETA-AAB). No patient was negative for both GPCR-AAB. In contrast, ETA-AAB and α1-AAB were absent in all (100%) and 9 (90%) of the 10 control patients, respectively. While α1-AAB targeted a specific epitope of the first extracellular loop of the α1-adrenergic receptor subtype A, an epitope of the second extracellular loop of the ETA receptor was identified as a target of ETA-AAB. As demonstrated in vitro, the functional activity of both autoantibodies found in prostate cancer can be neutralized by the aptamer BC007.ConclusionsWe hypothesized that α1-AAB and ETA-AAB, which are highly present in prostate cancer patients, could by their functional activity support carcinogenesis by excessive receptor stimulation. The in vitro demonstrated neutralization of α1- and ETA-AAB by the aptamer BC007 could open the door to complement the treatments already available for prostate cancer.

PBT2 inhibits glutamate-induced excitotoxicity in neurons through metal-mediated preconditioning

Excitotoxicity is the pathological process by which neuronal death occurs as a result of excessive stimulation of receptors at the excitatory synapse such as the NMDA receptor (NMDAR). Excitotoxicity has been implicated in the acute neurological damage from ischemia and traumatic brain injury and in the chronic neurodegeneration in Alzheimer's disease (AD) and Huntington's disease (HD). As a result NMDAR antagonists have become an attractive therapeutic strategy for the potential treatment of multiple neurodegenerative diseases. However NMDAR signaling is dichotomous in nature, with excessive increases in neuronal intracellular calcium through excessive NMDAR activity being lethal but moderate increases to intracellular calcium levels during normal synaptic function providing neuroprotection. Subsequently indiscriminant inhibition of this receptor is best avoided as was concluded from previous clinical trials of NMDAR antagonists. We show that the metal chaperone, PBT2, currently in clinical trials for HD, is able to protect against glutamate-induced excitotoxicity mediated through NMDARs. This was achieved by PBT2 inducing Zn2+-dependent increases in intracellular Ca2+ levels resulting in preconditioning of neurons and inhibition of Ca2+-induced neurotoxic signaling cascade involving calpain-activated cleavage of calcineurin. Our study demonstrates that modulating intracellular Ca2+ levels by a zinc ionophore is a valid therapeutic strategy to protect against the effects of excitotoxicity thought to underlie both acute and chronic neurodegenerative diseases.

Neuroplastic changes in addiction

Neuroplastic changes in addiction

Somatostatin (SS), SS receptors and SS analog treatment in tumorigenesis

Somatostatin (SS) is an inhibitory tetradecapeptide hormone with exocrine, endocrine, paracrine, and autocrine activities, which plays an important regulatory role in several cell functions, includin g inhibition of endocrine secretion and cell prolifer ation. Most of the effects of SS and of its currently avai lable analogs are mediated via five different G proteincoupled receptor (GPCRs), codenamed sst 1-5. SS receptors (sst s) are expressed in a tissue- and subtypeselective manner in both normal and neoplastic cell s, and the majority of SS target tissues express multi ple sst s. Recent data suggest that when sst s are coexpressed, they may interact forming homo- and hetero-dimers also with other GPCRs, thus altering their original pharmacological and functional profiles. The format ion of dimers can be not only constitutive, but also li gandpromoted: hence, compounds with high affinity for t he different receptor subtypes can be used to achieve effects elicited by specific dimers. A feature comm on to most GPCRs is the cyclic process of signaling, desensitization, internalization, resensitization, and recycling to the plasma membrane. These events prevent cells from undergoing excessive receptor stimulation or periods of prolonged inactivity. SS receptors differently internalize after agonist bin ding and, specifically, sst 2, sst 3 and sst 5 are internalized to a greater extent than sst 1 or sst 4. sst s are linked to several second messenger systems which are involved in their downstream intracellular response ( i.e., adenylyl cyclase, calcium and potassium ion channels, Na + /H

Dopaminergic Modulation of Afferent Synaptic Transmission in the Semicircular Canals of Frogs

Using multiunit recording of action potentials from the whole nerve with the aid of external perfusion, we investigated the effects of dopamine (DOP) agonists that are involved in modulatory actions on synaptic transmission in the isolated labyrinth preparations of frogs. The external application of DOP (0.1–1 mM), the D₁ agonist chloro-APB hydrobromide (CAPB, 50–100 μM) and the D₂ agonist quinerolane (QUI, 50–100 μM) induced a dose-dependent and reversible decline in the resting discharge frequency. In this concentration range, the potency of applied CAPB considerably exceeded that of QUI. AMPA, NMDA and ACPD responses were inhibited by the D₁ and D₂ agonists, implicating both subtypes of DOP receptors in the modulation of both ionotropic and metabotropic glutamate receptors. The inhibitory action of the DOP agonists on L-glutamate responses persisted in a high Mg²⁺ solution in conditions of selective activation of the postsynaptic membrane. The results obtained suggest that DOP may interact with both D₁ and D₂ receptor subtypes, most likely located postsynaptically on the afferent nerve fibers. This dopaminergic control mechanism may result in the reduction of the activated firing rate, thus preventing over-excitation and excitotoxic injury of the afferent dendrites after the external application of L-glutamate and excessive receptor stimulation.

CEREBRAL CORRELATES OF ABERRANT TRANSCRIPTION OF HERV-W GAG ELEMENTS IN THE CEREBROSPINAL FLUID OF PATIENTS WITH FIRST-EPISODE SCHIZOPHRENIA SPECTRUM DISORDER

The N-methyl-d-aspartate (NMDA) subtype of glutamate receptors plays an important role in brain physiology, but excessive receptor stimulation results in seizures and excitotoxic nerve cell death. NMDA receptor-mediated neuronal excitation and injury can be prevented by high, non-physiological concentrations of the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA). Here we report that endogenous KYNA, which is formed in and released from astrocytes, controls NMDA receptors in vivo. This was revealed with the aid of the dopaminergic drugs d-amphetamine and apomorphine, which cause rapid, transient decreases in striatal KYNA levels in rats. Intrastriatal injections of the excitotoxins NMDA or quinolinate (but not the non-NMDA receptor agonist kainate) at the time of maximal KYNA reduction resulted in two- to threefold increases in excitotoxic lesion size. Pre-treatment with a kynurenine 3-hydroxylase inhibitor or with dopamine receptor antagonists, i.e., two classes of pharmacological agents that prevented the reduction in brain KYNA caused by dopaminergic stimulation, abolished the potentiation of neurotoxicity. Thus, the present study identifies a previously unappreciated role of KYNA as a functional link between dopamine receptor stimulation and NMDA neurotoxicity in the striatum.

Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal N-methyl-d-aspartate neurotoxicity

The N-methyl-d-aspartate (NMDA) subtype of glutamate receptors plays an important role in brain physiology, but excessive receptor stimulation results in seizures and excitotoxic nerve cell death. NMDA receptor-mediated neuronal excitation and injury can be prevented by high, non-physiological concentrations of the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA). Here we report that endogenous KYNA, which is formed in and released from astrocytes, controls NMDA receptors in vivo. This was revealed with the aid of the dopaminergic drugs d-amphetamine and apomorphine, which cause rapid, transient decreases in striatal KYNA levels in rats. Intrastriatal injections of the excitotoxins NMDA or quinolinate (but not the non-NMDA receptor agonist kainate) at the time of maximal KYNA reduction resulted in two- to threefold increases in excitotoxic lesion size. Pre-treatment with a kynurenine 3-hydroxylase inhibitor or with dopamine receptor antagonists, i.e., two classes of pharmacological agents that prevented the reduction in brain KYNA caused by dopaminergic stimulation, abolished the potentiation of neurotoxicity. Thus, the present study identifies a previously unappreciated role of KYNA as a functional link between dopamine receptor stimulation and NMDA neurotoxicity in the striatum.

CB1 receptor knockout mice show similar behavioral modifications to wild-type mice when enkephalin catabolism is inhibited

Behavioral and biochemical studies have suggested a functional link between the endogenous cannabinoid and opioid systems. Different hypotheses have been proposed to explain the interactions between opioid and cannabinoid systems such as a common pathway stimulating the dopaminergic system, a facilitation of signal-transduction- and/or a cannabinoid-induced enhancement of opioid peptide release. However, at this time, all the studies have been performed with exogenous agonists (delta-9-tetrahydrocannabinol or morphine), leading to a generally excessive stimulation of receptors normally stimulated by endogenous effectors (anandamide or opioid peptides) in various brain structures. To overcome this problem, we have measured various behavioral responses induced by the stimulation of the endogenous opioid system using the dual inhibitor of enkephalin-degrading enzymes, RB101, in CB1 receptor knockout mice. Thus, analgesia, locomotor activity, anxiety and antidepressant-like effects were measured after RB101 administration (80 and 120 mg/kg i.p. or 10 mg/kg, i.v.) in CB1 receptor knockout mice and their wild-type littermates. In all the experiments, inhibition of enkephalin catabolism produced similar modifications in behavior observed in CB1 knockout and wild-type mice. These results suggest limited physiological interaction between cannabinoid and opioid systems.

Arrestin-independent internalization of G protein-coupled receptors.

A feature common to most G protein-coupled receptors (GPCRs) is the cyclic process of signaling, desensitization, internalization, resensitization, and recycling to the plasma membrane. These coordinated events prevent cells from undergoing excessive receptor stimulation or periods of prolonged

Desensitization of neuronal nicotinic receptors.

The loss of functional response upon continuous or repeated exposure to agonist, desensitization, is an intriguing phenomenon if not as yet a well-defined physiological mechanism. However, detailed evaluation of the properties of desensitization, especially for the superfamily of ligand-gated ion channels, reveals how the nervous system could make important use of this process that goes far beyond simply curtailing excessive receptor stimulation and the prevention of excitotoxicity. Here we will review the mechanistic basis of desensitization and discuss how the subunit-dependent properties and regulation of nicotinic acetylcholine receptor (nAChR) desensitization contribute to the functional diversity of these channels. These studies provide the essential framework for understanding how the physiological regulation of desensitization could be a major determinant of synaptic efficacy by controlling, in both the short and long term, the number of functional receptors. This type of mechanism can be extended to explain how the continuous occupation of desensitized receptors during chronic nicotine exposure contributes to drug addiction, and highlights the potential significance of prolonged nAChR desensitization that would also occur as a result of extended acetylcholine lifetime during treatment of Alzheimer's disease with cholinesterase inhibitors. Thus, a clearer picture of the importance of nAChR desensitization in both normal information processing and in various diseased states is beginning to emerge.

Molecular basis of glutamate toxicity in retinal ganglion cells

Loss of retinal ganglion cells (RGCs) is a hallmark of many ophthalmic diseases including glaucoma, retinal ischemia due to central artery occlusion, anterior ischemic optic neuropathy and may be significant in optic neuritis, optic nerve trauma, and AIDS. Recent research indicates that neurotoxicity is caused by excessive stimulation of receptors for excitatory amino acids (EAAs). In particular, the amino acid glutamate has been shown to act as a neurotoxin which exerts its toxic effect on RGCs predominantly through the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. NMDA-receptor-mediated toxicity in RGCs is dependent on the influx of extracellular Ca2+. The increase in [Ca2+]i acts as a second messenger that sets in motion the cascade leading to eventual cell death. Glutamate stimulates its own release in a positive feedback loop by its interaction with the non-NMDA receptor subtypes. Ca(2+)-induced Ca2+ release and further influx of Ca2+ through voltage-gated Ca2+ channels after glutamate-induced depolarization contribute to glutamate toxicity. In vitro and in vivo studies suggest that the use of selective NMDA receptor antagonists or Ca2+ channel blockers should be useful in preventing or at least abating neuronal loss in the retina. Of particular importance for future clinical use of NMDA receptor antagonists in the treatment of acute vascular insults is the finding that some drugs can prevent glutamate-induced neurotoxicity, even when administered a few hours after the onset of retinal ischemia.