QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.108.046623v1 74/2/348    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Dickinson, J. A. Articles by Wonnacott, S. PubMed PubMed Citation Articles by Dickinson, J. A. Articles by Wonnacott, S.

Presynaptic 7- and β2-Containing Nicotinic Acetylcholine Receptors Modulate Excitatory Amino Acid Release from Rat Prefrontal Cortex Nerve Terminals via Distinct Cellular Mechanisms

Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom (J.A.D., S.W.); and Psychiatry Discovery Technology Group, GlaxoSmithKline, Harlow, Essex, United Kingdom (J.N.C.K.)

Nicotine can enhance working memory and attention. Activation of both 7 and β2^* 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 β2^* nAChR-mediated [³H]D-aspartate release from the PFC in vitro. Using the 7 and β2^* 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 Ca²⁺ channels (VOCCs) and intracellular Ca²⁺ stores, we show that [³H]D-aspartate release evoked by activation of β2^* nAChRs occurs via VOCCs. In contrast, 7 nAChR-evoked release was unaffected by VOCC blockers but was abolished by modulators of Ca²⁺ stores, including ryanodine. The 7 nAChR ligand -bungarotoxin and ryanodine receptors were colocalized to a subpopulation of PFC synaptosomes. Compound A-evoked [³H]D-aspartate release was also blocked by mitogen-activated protein kinase kinase 1 inhibitors, implicating extracellular signal-regulated kinase (ERK)1/2 in 7 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, β2^* and 7 nAChR subtypes in the PFC mediate [³H]D-aspartate release via distinct mechanisms as a result of their differential coupling to VOCCs and Ca²⁺-induced Ca²⁺ 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.

Address correspondence to: Prof. Susan Wonnacott, Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom. E-mail: bsssw{at}bath.ac.uk