Functional responses and subunit composition of presynaptic nicotinic receptor subtypes explored using the novel agonist 5-iodo-A-85380

Mogg, Adrian J.; Jones, F. Avery; Pullar, Ian A.; Sharples, Christopher G. V.; Wonnacott, Susan

doi:10.1016/j.neuropharm.2004.06.013

Cited by 28 publications

(26 citation statements)

References 43 publications

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“…Functional assays with sazetidine-A on native rat nAChRs have therefore been performed to answer this specific question. Dopamine release from rat striatal slices is mediated by the activation of native ␣4␤2* and ␣6␤2* nAChRs (Mogg et al, 2004;Salminen et al, 2004;Grady et al, 2007;Smith et al, 2007). We found that sazetidine-A acts as a potent and efficacious agonist in evoking […”

Section: Resultsmentioning

confidence: 99%

Sazetidine-A Is a Potent and Selective Agonist at Native and Recombinant α4β2 Nicotinic Acetylcholine Receptors

Zwart

Carbone²,

Moroni³

et al. 2008

Mol Pharmacol

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129

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Sazetidine-A has been recently proposed to be a "silent desensitizer" of ␣4␤2 nicotinic acetylcholine receptors (nAChRs), implying that it desensitizes ␣4␤2 nAChRs without first activating them. This unusual pharmacological property of sazetidine-A makes it, potentially, an excellent research tool to distinguish between the role of activation and desensitization of ␣4␤2 nAChRs in mediating the central nervous system effects of nicotine itself, as well as those of new nicotinic drugs. We were surprised to find that sazetidine-A potently and efficaciously stimulated nAChR-mediated dopamine release from rat striatal slices, which is mediated by ␣4␤2* and ␣6␤2* subtypes of nAChR. The agonist effects on native striatal nAChRs prompted us to re-examine the effects of sazetidine-A on recombinant ␣4␤2 nAChRs in more detail. We expressed the two alternative stoichiometries of ␣4␤2 nAChR in Xenopus laevis oocytes and investigated the agonist properties of sazetidine-A on both ␣4(2)␤2(3)and ␣4(3)␤2(2) nAChRs. We found that sazetidine-A potently activated both stoichiometries of ␣4␤2 nAChR: it was a full agonist on ␣4(2)␤2(3) nAChRs, whereas it had an efficacy of only 6% on ␣4(3)␤2(2) nAChRs. In contrast to what has been published before, we therefore conclude that sazetidine-A is an agonist of native and recombinant ␣4␤2 nAChRs but shows differential efficacy on ␣4␤2 nAChRs subtypes.

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Section: Resultsmentioning

confidence: 99%

Sazetidine-A Is a Potent and Selective Agonist at Native and Recombinant α4β2 Nicotinic Acetylcholine Receptors

Zwart

Carbone²,

Moroni³

et al. 2008

Mol Pharmacol

Self Cite

100

129

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“…5-I-A-85380 preferentially activates ␣4␤2-or ␣6␤2-containing nAChRs (Mukhin et al, 2000;Mogg et al, 2004). In PFC synaptosomes, ␣4␤2* nAChRs are likely to mediate the effects of nanomolar concentrations of 5-I-A-85380 on […”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the ␤2*-selective nAChR antagonist DH␤E (1 M) had no significant effect on compound A-evoked [ ␤2* nAChRs have also been implicated in excitatory amino acid release from frontal cortex (Gioanni et al, 1999;Rousseau et al, 2005). 5-Iodo-A-85380 is a potent ␤2*-selective nAChR agonist (Mukhin et al, 2000;Mogg et al, 2004;Fig. 1A, right inset) that was approximately 300 times less potent than compound A in displacing 125 I-␣Bgt binding to PFC membranes (K i value of 10.7 Ϯ 1.1 M; Fig. 1A).…”

Section: ␣7 and Non-␣7 Nachrsmentioning

confidence: 93%

Presynaptic α7- and β2-Containing Nicotinic Acetylcholine Receptors Modulate Excitatory Amino Acid Release from Rat Prefrontal Cortex Nerve Terminals via Distinct Cellular Mechanisms

Dickinson

Kew²,

Wonnacott³

2008

Mol Pharmacol

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149

120

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Nicotine can enhance working memory and attention. Activation of both ␣7 and ␤2* nicotinic acetylcholine receptors (nAChRs) in the prefrontal cortex (PFC) has been implicated in these processes. The ability of presynaptic nAChRs to modulate neurotransmitter release, notably glutamate release, is postulated to contribute to nicotine's effects. We have examined the cellular mechanisms underlying ␣7 and ␤2* nAChR-mediated ]D-aspartate release was also blocked by mitogen-activated protein kinase kinase 1 inhibitors, implicating extracellular signal-regulated kinase (ERK)1/2 in ␣7 nAChRevoked exocytosis. Western blotting confirmed that compound A, but not 5-iodo-A-85380, application increased ERK2 phosphorylation in PFC synaptosomes, and this was dependent on ryanodine-sensitive stores. Compound A also promoted synapsin-1 phosphorylation at ERK1/2-dependent sites, in a ryanodine-sensitive manner. Thus, ␤2* and ␣7 nAChR subtypes in the PFC mediate [3 H]D-aspartate release via distinct mechanisms as a result of their differential coupling to VOCCs and Ca 2ϩ -induced Ca 2ϩ release (CICR), respectively. The ability of ␣7 nAChRs to promote the phosphorylation of presynaptic ERK2 and synapsin-1, downstream of CICR, provides a potential mechanism for presynaptic facilitation in the PFC.

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“…Several different compounds have therefore been developed and tested in humans to specifically label the α4 nAChRs in the brain by PET, e.g., 2-and 6-[ 18 F] fluoro-A-85380 (Ding et al 2004;Gallezot et al 2005;Nordberg 2006). In vitro binding studies with these ligands indicate very high affinity for α4β2 nAChR subunits (Gundisch et al 2005), although affinity for the α6β2 nAChR subtype could not be excluded (Mogg et al 2004). Nevertheless, the major drawback with the 2-and the 6-[ 18 F] fluoro-A-85380 tracers is the considerably longer scanning time (7-8 h) than with 11 C-nicotine (1 h or less).…”

Section: Discussionmentioning

confidence: 99%

Changes in brain 11C–nicotine binding sites in patients with mild Alzheimer’s disease following rivastigmine treatment as assessed by PET

et al. 2007

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Functional responses and subunit composition of presynaptic nicotinic receptor subtypes explored using the novel agonist 5-iodo-A-85380

Cited by 28 publications

References 43 publications

Sazetidine-A Is a Potent and Selective Agonist at Native and Recombinant α4β2 Nicotinic Acetylcholine Receptors

Sazetidine-A Is a Potent and Selective Agonist at Native and Recombinant α4β2 Nicotinic Acetylcholine Receptors

Presynaptic α7- and β2-Containing Nicotinic Acetylcholine Receptors Modulate Excitatory Amino Acid Release from Rat Prefrontal Cortex Nerve Terminals via Distinct Cellular Mechanisms

Changes in brain 11C–nicotine binding sites in patients with mild Alzheimer’s disease following rivastigmine treatment as assessed by PET

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