Mode of action of the positive modulator PNU-120596 on α7 nicotinic acetylcholine receptors

Szabó, Alexandra; Pesti, Krisztina; Mike, Arpad; Vizi, E. Sylvester

doi:10.1016/j.neuropharm.2014.01.033

Cited by 21 publications

(27 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, it has been proposed that PNU-120596 binds predominantly to a fast desensitized state and induces a set of conformations in which the opening of the pore is energetically more favorable (Szabo et al, 2014). On the other hand, only the decrease in the energetic barrier for opening has been proposed as the underlying mechanism for enhancement of peak currents by type I PAMs (Williams et al, 2011b;Hurst et al, 2013).…”

Section: Modulatory Sites Pnu-120596mentioning

confidence: 99%

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

2016

View full text Add to dashboard Cite

The nicotinic acetylcholine receptor (nAChR) belongs to a superfamily of pentameric ligand-gated ion channels involved in many physiologic and pathologic processes. Among nAChRs, receptors comprising the a7 subunit are unique because of their high Ca 21 permeability and fast desensitization. nAChR agonists elicit a transient ion flux response that is further sustained by the release of calcium from intracellular sources. Owing to the dual ionotropic/metabotropic nature of a7 receptors, signaling pathways are activated. The a7 subunit is highly expressed in the nervous system, mostly in regions implicated in cognition and memory and has therefore attracted attention as a novel drug target. Additionally, its dysfunction is associated with several neuropsychiatric and neurologic disorders, such as schizophrenia and Alzheimer's disease. a7 is also expressed in non-neuronal cells, particularly immune cells, where it plays a role in immunity, inflammation, and neuroprotection. Thus, a7 potentiation has emerged as a therapeutic strategy for several neurologic and inflammatory disorders. With unique activation properties, the receptor is a sensitive drug target carrying different potential binding sites for chemical modulators, particularly agonists and positive allosteric modulators. Although macroscopic and singlechannel recordings have provided significant information about the underlying molecular mechanisms and binding sites of modulatory compounds, we know just the tip of the iceberg. Further concerted efforts are necessary to effectively exploit a7 as a drug target for each pathologic situation. In this article, we focus mainly on the molecular basis of activation and drug modulation of a7, key pillars for rational drug design.

show abstract

Section: Modulatory Sites Pnu-120596mentioning

confidence: 99%

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

2016

View full text Add to dashboard Cite

show abstract

“…For example, in the 5-HT 3 receptor, the extent of receptor desensitization was positively correlated with the polarity of the amino acid residue at the 427 0 position in the MAS (Hu et al, 2006). Even more recently, some chemicals, such as PNU-120596, were found to be closely associated with the channelgating kinetics (Kalappa et al, 2013;Pesti et al, 2014;Szabo et al, 2014). Despite previous intense investigation, the structural basis for the functional coupling of agonist binding to channel gating, which results in channel opening and desensitization, is still unclear (Giniatullin et al, 2005;Katz and Thesleff, 1957).…”

Section: )mentioning

confidence: 99%

The coupling interface and pore domain codetermine the single-channel activity of the α7 nicotinic receptor

et al. 2015

View full text Add to dashboard Cite

“…This may have been due to the higher dose actually driving the α7 nicotinic receptors into desensitization (Adler et al 1998). Studies have shown that administration of PNU-120596 significantly slowed the dissociation of choline from α7 nicotinic receptors (Szabo et al 2014), thus increasing the probability of desensitization. As was seen with PNU-120596 alone, administered to DBA/2 mice, the decrease in TC ratio was driven primarily by an increase in conditioning amplitude, but also coupled, in this case, with a decrease in test amplitude.…”

Section: Discussionmentioning

confidence: 99%

“…As noted before, DBA/2 mice are reduced by ~30% while C3H Chrna7 heterozygote mice are reduced by 50–60%. One study proposed that when an agonist is present, PNU-120596 binds to the receptor, inducing desensitization but trapping the agonist within its binding site such that when the receptor resensitizes, it is again activated (Szabo et al 2014). Thus, since DBA/2 mice have more receptors such that a greater number resensitized and were reactivated there was a prolonged effect.…”

Section: Discussionmentioning

confidence: 99%

Maximizing the effect of an α7 nicotinic receptor PAM in a mouse model of schizophrenia-like sensory inhibition deficits

Stevens¹,

Zheng²,

Floyd³

et al. 2015

Brain Research

View full text Add to dashboard Cite

Positive allosteric modulators (PAMs) for the α7 nicotinic receptor hold promise for the treatment of sensory inhibition deficits observed in schizophrenia patients. Studies of these compounds in the DBA/2 mouse, which models the schizophrenia-related deficit in sensory inhibition, have shown PAMs to be effective in improving the deficit. However, the first published clinical trial of a PAM for both sensory inhibition deficits and related cognitive difficulties failed, casting a shadow on this therapeutic approach. The present study used both DBA/2 mice, and C3H Chrna7 heterozygote mice to assess the ability of the α7 PAM, PNU-120596, to improve sensory inhibition. Both of these strains of mice have reduced hippocampal α7 nicotinic receptor numbers and deficient sensory inhibition similar to schizophrenia patients. Low doses of PNU-120596 (1 or 3.33 mg/kg) were effective in the DBA/2 mouse but not the C3H Chrna7 heterozygote mouse. Moderate doses of the selective α7 nicotinic receptor agonist, choline chloride (10 or 33 mg/kg), were also ineffective in improving sensory inhibition in the C3H Chrna7 heterozygote mouse. However, combining the lowest doses of both PNU-120596 and choline chloride in this mouse model did improve sensory inhibition. We propose here that the difference in efficacy of PNU-120596 between the 2 mouse strains is driven by differences in hippocampal α7 nicotinic receptor numbers, such that C3H Chrna7 heterozygote mice require additional direct stimulation of the α7 receptors. These data may have implications for further clinical testing of putative α7 nicotinic receptor PAMs.

show abstract

Mode of action of the positive modulator PNU-120596 on α7 nicotinic acetylcholine receptors

Cited by 21 publications

References 33 publications

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

The coupling interface and pore domain codetermine the single-channel activity of the α7 nicotinic receptor

Maximizing the effect of an α7 nicotinic receptor PAM in a mouse model of schizophrenia-like sensory inhibition deficits

Contact Info

Product

Resources

About