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Presynaptic alpha 7- and beta 2-containing nicotinic acetylcholine receptors modulate excitatory amino acid release from rat prefrontal cortex nerve terminals via distinct cellular mechanisms.
Mol Pharmacol. 2008 Aug; 74(2):348-59.MP

Abstract

Nicotine can enhance working memory and attention. Activation of both alpha7 and beta2(*) 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 alpha7 and beta2(*) nAChR-mediated [(3)H]d-aspartate release from the PFC in vitro. Using the alpha7 and beta2(*) nAChR-selective agonists (R)-N-(1-azabicyclo[2.2.2]-oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide) (compound A) and 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-iodo-A-85380), respectively, in conjunction with inhibitors of voltage-operated Ca(2+) channels (VOCCs) and intracellular Ca(2+) stores, we show that [(3)H]d-aspartate release evoked by activation of beta2(*) nAChRs occurs via VOCCs. In contrast, alpha7 nAChR-evoked release was unaffected by VOCC blockers but was abolished by modulators of Ca(2+) stores, including ryanodine. The alpha7 nAChR ligand alpha-bungarotoxin and ryanodine receptors were colocalized to a subpopulation of PFC synaptosomes. Compound A-evoked [(3)H]d-aspartate release was also blocked by mitogen-activated protein kinase kinase 1 inhibitors, implicating extracellular signal-regulated kinase (ERK)1/2 in alpha7 nAChR-evoked 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, beta2(*) and alpha7 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(2+)-induced Ca(2+) release (CICR), respectively. The ability of alpha7 nAChRs to promote the phosphorylation of presynaptic ERK2 and synapsin-1, downstream of CICR, provides a potential mechanism for presynaptic facilitation in the PFC.

Authors+Show Affiliations

Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom.No affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18445710

Citation

Dickinson, Jane A., et al. "Presynaptic Alpha 7- and Beta 2-containing Nicotinic Acetylcholine Receptors Modulate Excitatory Amino Acid Release From Rat Prefrontal Cortex Nerve Terminals Via Distinct Cellular Mechanisms." Molecular Pharmacology, vol. 74, no. 2, 2008, pp. 348-59.
Dickinson JA, Kew JN, Wonnacott S. Presynaptic alpha 7- and beta 2-containing nicotinic acetylcholine receptors modulate excitatory amino acid release from rat prefrontal cortex nerve terminals via distinct cellular mechanisms. Mol Pharmacol. 2008;74(2):348-59.
Dickinson, J. A., Kew, J. N., & Wonnacott, S. (2008). Presynaptic alpha 7- and beta 2-containing nicotinic acetylcholine receptors modulate excitatory amino acid release from rat prefrontal cortex nerve terminals via distinct cellular mechanisms. Molecular Pharmacology, 74(2), 348-59. https://doi.org/10.1124/mol.108.046623
Dickinson JA, Kew JN, Wonnacott S. Presynaptic Alpha 7- and Beta 2-containing Nicotinic Acetylcholine Receptors Modulate Excitatory Amino Acid Release From Rat Prefrontal Cortex Nerve Terminals Via Distinct Cellular Mechanisms. Mol Pharmacol. 2008;74(2):348-59. PubMed PMID: 18445710.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Presynaptic alpha 7- and beta 2-containing nicotinic acetylcholine receptors modulate excitatory amino acid release from rat prefrontal cortex nerve terminals via distinct cellular mechanisms. AU - Dickinson,Jane A, AU - Kew,James N C, AU - Wonnacott,Susan, Y1 - 2008/04/29/ PY - 2008/5/1/pubmed PY - 2008/8/23/medline PY - 2008/5/1/entrez SP - 348 EP - 59 JF - Molecular pharmacology JO - Mol. Pharmacol. VL - 74 IS - 2 N2 - Nicotine can enhance working memory and attention. Activation of both alpha7 and beta2(*) 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 alpha7 and beta2(*) nAChR-mediated [(3)H]d-aspartate release from the PFC in vitro. Using the alpha7 and beta2(*) nAChR-selective agonists (R)-N-(1-azabicyclo[2.2.2]-oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide) (compound A) and 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-iodo-A-85380), respectively, in conjunction with inhibitors of voltage-operated Ca(2+) channels (VOCCs) and intracellular Ca(2+) stores, we show that [(3)H]d-aspartate release evoked by activation of beta2(*) nAChRs occurs via VOCCs. In contrast, alpha7 nAChR-evoked release was unaffected by VOCC blockers but was abolished by modulators of Ca(2+) stores, including ryanodine. The alpha7 nAChR ligand alpha-bungarotoxin and ryanodine receptors were colocalized to a subpopulation of PFC synaptosomes. Compound A-evoked [(3)H]d-aspartate release was also blocked by mitogen-activated protein kinase kinase 1 inhibitors, implicating extracellular signal-regulated kinase (ERK)1/2 in alpha7 nAChR-evoked 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, beta2(*) and alpha7 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(2+)-induced Ca(2+) release (CICR), respectively. The ability of alpha7 nAChRs to promote the phosphorylation of presynaptic ERK2 and synapsin-1, downstream of CICR, provides a potential mechanism for presynaptic facilitation in the PFC. SN - 1521-0111 UR - https://www.unboundmedicine.com/medline/citation/18445710/Presynaptic_alpha_7__and_beta_2_containing_nicotinic_acetylcholine_receptors_modulate_excitatory_amino_acid_release_from_rat_prefrontal_cortex_nerve_terminals_via_distinct_cellular_mechanisms_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=18445710 DB - PRIME DP - Unbound Medicine ER -