86Rb+ efflux mediated by α4β2*-nicotinic acetylcholine receptors with high and low-sensitivity to stimulation by acetylcholine display similar agonist-induced desensitization

Marks, Michael J.; Meinerz, Natalie M.; Brown, Rob; Collins, Allan C.

doi:10.1016/j.bcp.2010.06.040

Cited by 30 publications

(34 citation statements)

References 55 publications

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“…Assuming a translation of the in vitro window current to an in vivo setting, such a persistent cholinergic activity could likely be a contributing phenomenon in volume transmission. Here, the wider window current at lower ACh concentrations observed with HS receptors [22,23] especially supports a role for this stoichiometry in this transmission mode.…”

Section: Modes Of Neurotransmission Of A4b2 Nachr Stoichiometriessupporting

confidence: 62%

“…It is thus believed to relate to the residual nAChR activity in a scenario of tonic exposure to an agonist, such as in volume transmission as described below, or upon administration of an exogenous nicotinic agonist. Here, it has been observed that the HS stoichiometry displays window current at lower and presumably more physiological agonist levels than the LS receptor [22,23]. Analogously, the window currents for various a4b2* agonists differ between the two stoichiometries [24].…”

Section: Molecular Aspects Of Nachrsmentioning

confidence: 71%

“…Both stoichiometries may contribute to neurotransmission in Renshaw cells in mouse spinal cord [54]. Finally, biphasic ACh concentration-response curves characterized by EC 50 values consistent with in vivo expression of HS and LS stoichiometries have been observed in mouse cortical and thalamic synaptosomes [23,55].…”

Section: Modes Of Neurotransmission Of A4b2 Nachr Stoichiometriesmentioning

confidence: 99%

“…The ACh window current (grey area) of the a4b2 nAChR is defined by the overlap of the receptor activation curve (solid line) and desensitization curve (dashed line) and indicates an agonist concentration range in which the receptor is expected to be tonically active. This has been addressed for a4b2 nAChR in multiple studies [14,[22][23][24].…”

Section: Molecular Aspects Of Nachrsmentioning

confidence: 99%

“…Furthermore, nAChR agonists are notoriously known for their bell-shaped pharmacology (e.g. [67]), which may be due to increased desensitization at higher doses [14,[22][23][24], thus making dosing of these drugs somewhat of a challenge.…”

Section: Drug Development Targeting A4b2 Nachrsmentioning

confidence: 99%

See 4 more Smart Citations

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

Grupe

Grunnet

Bastlund

et al. 2014

Basic Clin Pharma Tox

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Abstract:The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels broadly involved in regulating neurotransmission in the central nervous system (CNS) by conducting cation currents through the membrane of neurons. Many different nAChR subtypes exist with each their functional characteristics, expression pattern and pharmacological profile. The focus of the present MiniReview is on the heteromeric a4b2 nAChR, as activity at this subtype contributes to cognitive functioning through interactions with multiple neurotransmitter systems and is implicated in various CNS disorders, for example schizophrenia and Alzheimer's disease. Additionally, the a4b2 nAChR provides an extra layer of molecular complexity by existing in two different stoichiometries determined by the subunit composition. Such findings have founded the rationale that pharmacological modulation of the a4b2 nAChR may be used as a treatment approach in various CNS disorders. As subtype-selective agonists and other cholinergic ligands have only shown limited therapeutic success, the focus of recent drug development endeavours has largely shifted to positive allosteric modulators (PAMs). By potentiating the action of an agonist through binding to an allosteric site, a PAM can enhance cholinergic neurotransmission, thus compensating for compromised neuronal communication in a pathophysiological setting. The pharmacological advantages of PAMs compared to other types of ligands include minimal interference with spatial and temporal aspects of neurotransmission as well as higher subtype selectivity, hypothetically resulting in high clinical efficacy with minimal adverse effects. In this MiniReview, we describe the currently identified compounds, which potentiate the effects of agonists at the a4b2 nAChR. The potential clinical advantages and concerns of PAMs are discussed in the light of the role of a4b2 nAChRs as key regulators of fast synaptic transmission.For decades, the a4b2 subtype of nicotinic acetylcholine (ACh) receptors (nAChRs) has been extensively investigated as a putative drug target in different therapeutic areas. Being widely involved in central neurotransmission as well as implicated in various pathophysiological states, much research has been aimed at developing pharmacological ligands targeting this subtype as a treatment approach in both psychiatric and neurodegenerative diseases [1][2][3][4][5]. The ligand class having received most attention within nAChR drug development aimed at diseases of the central nervous system (CNS) is subtype-selective agonists [1]. However, the success of these efforts must so far be considered limited as the only a4b2 ligands currently approved for medical use are the partial a4b2 nAChR agonists, varenicline and cytisine [6], which are used as smoking cessation aids. This has set off a drug hunt for novel types of modulators targeting the a4b2 nAChR as well as other subtypes of the nAChR family, where the focus has switched from agonists to positive allosteric modulators (PAMs) of the recepto...

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Section: Modes Of Neurotransmission Of A4b2 Nachr Stoichiometriessupporting

confidence: 62%

Section: Molecular Aspects Of Nachrsmentioning

confidence: 71%

Section: Modes Of Neurotransmission Of A4b2 Nachr Stoichiometriesmentioning

confidence: 99%

Section: Molecular Aspects Of Nachrsmentioning

confidence: 99%

Section: Drug Development Targeting A4b2 Nachrsmentioning

confidence: 99%

See 3 more Smart Citations

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

Grupe

Grunnet

Bastlund

et al. 2014

Basic Clin Pharma Tox

View full text Add to dashboard Cite

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Nicotinic acetylcholine receptors in attention circuitry: the role of layer VI neurons of prefrontal cortex

Proulx

Piva

Tian

et al. 2013

Cell. Mol. Life Sci.

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Cholinergic modulation of prefrontal cortex is essential for attention. In essence, it focuses the mind on relevant, transient stimuli in support of goal-directed behavior. The excitation of prefrontal layer VI neurons through nicotinic acetylcholine receptors optimizes local and top-down control of attention. Layer VI of prefrontal cortex is the origin of a dense feedback projection to the thalamus and is one of only a handful of brain regions that express the α5 nicotinic receptor subunit, encoded by the gene chrna5. This accessory nicotinic receptor subunit alters the properties of high-affinity nicotinic receptors in layer VI pyramidal neurons in both development and adulthood. Studies investigating the consequences of genetic deletion of α5, as well as other disruptions to nicotinic receptors, find attention deficits together with altered cholinergic excitation of layer VI neurons and aberrant neuronal morphology. Nicotinic receptors in prefrontal layer VI neurons play an essential role in focusing attention under challenging circumstances. In this regard, they do not act in isolation, but rather in concert with cholinergic receptors in other parts of prefrontal circuitry. This review urges an intensification of focus on the cellular mechanisms and plasticity of prefrontal attention circuitry. Disruptions in attention are one of the greatest contributing factors to disease burden in psychiatric and neurological disorders, and enhancing attention may require different approaches in the normal and disordered prefrontal cortex.

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Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons

et al. 2021

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Neonicotinoid pesticides, originally developed to target the insect nervous system, have been reported to interact with human receptors and to activate rodent neurons. Therefore, we evaluated in how far these compounds may trigger signaling in human neurons, and thus, affect the human adult or developing nervous system. We used SH-SY5Y neuroblastoma cells as established model of nicotinic acetylcholine receptor (nAChR) signaling. In parallel, we profiled dopaminergic neurons, generated from LUHMES neuronal precursor cells, as novel system to study nAChR activation in human post-mitotic neurons. Changes of the free intracellular Ca2+ concentration ([Ca2+]i) were used as readout, and key findings were confirmed by patch clamp recordings. Nicotine triggered typical neuronal signaling responses that were blocked by antagonists, such as tubocurarine and mecamylamine. Pharmacological approaches suggested a functional expression of α7 and non-α7 nAChRs on LUHMES cells. In this novel test system, the neonicotinoids acetamiprid, imidacloprid, clothianidin and thiacloprid, but not thiamethoxam and dinotefuran, triggered [Ca2+]i signaling at 10–100 µM. Strong synergy of the active neonicotinoids (at low micromolar concentrations) with the α7 nAChR-positive allosteric modulator PNU-120596 was observed in LUHMES and SH-SY5Y cells, and specific antagonists fully inhibited such signaling. To provide a third line of evidence for neonicotinoid signaling via nAChR, we studied cross-desensitization: pretreatment of LUHMES and SH-SY5Y cells with active neonicotinoids (at 1–10 µM) blunted the signaling response of nicotine. The pesticides (at 3–30 µM) also blunted the response to the non-α7 agonist ABT 594 in LUHMES cells. These data show that human neuronal cells are functionally affected by low micromolar concentrations of several neonicotinoids. An effect of such signals on nervous system development is a toxicological concern.

show abstract

86Rb+ efflux mediated by α4β2*-nicotinic acetylcholine receptors with high and low-sensitivity to stimulation by acetylcholine display similar agonist-induced desensitization

Cited by 30 publications

References 55 publications

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

Nicotinic acetylcholine receptors in attention circuitry: the role of layer VI neurons of prefrontal cortex

Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons

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