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The role of N-, Q- and R-type Ca2+ channels in feedback inhibition of ACh release from rat basal forebrain neurones

By T G J Allen


The Ca2+ channel subtypes controlling ACh release from basal forebrain neurones and the ionic basis underlying muscarinic receptor-mediated autoinhibition were studied using skeletal myoballs to detect ACh release from individual rat basal forebrain neurones in culture.Somatic Ca2+ currents evoked using a simulated action potential waveform revealed that Ca2+ entry was primarily through N-, Q- and to a lesser extent R-, T- and L-type Ca2+ channels.Muscarine (10 μm) inhibited N- and Q- but not R-, T- or L-type somatic Ca2+ channels. Agonist inhibition was totally blocked by pre-treatment with pertussis toxin (500 ng ml−1).ACh release from discrete sites along basal forebrain neurites (1.2 mm extracellular Ca2+) could be largely abolished by blocking Ca2+ entry through either N-type or Q-type Ca2+ channels. Inhibition of Ca2+ entry through L- or T-type channels had no effect upon release. Following inhibition of either N- or Q-type Ca2+ channels, release could be restored to near control levels by raising [Ca2+]o. After selectively blocking N-, Q-, L- and T-type channels, low levels of release could still be evoked as a result of Ca2+ entry through R-type Ca2+ channels.Muscarinic receptor activation reversibly inhibited ACh release due to Ca2+ entry through N-, Q- and R-type Ca2+ channels. In contrast, inhibition of inwardly rectifying K+ channels using Ba2+ (3–10 μm) or substance P (0.03–0.1 μm), or block of SK or BK Ca2+-activated K+ channels with apamin (100 nm) or charbydotoxin (100 nm) respectively, had no effect upon either ACh release or its modulation by muscarinic agonists.These results show that ACh release from individual release sites on basal forebrain neurones is controlled by multiple Ca2+ channel subtypes with overlapping Ca2+ microdomains and that autoinhibition of release results from M2 muscarinic receptor-mediated inhibition of these presynaptic Ca2+ channels rather than as a consequence of K+ channel activation

Topics: Original Articles
Publisher: Blackwell Science Inc
OAI identifier: oai:pubmedcentral.nih.gov:2269139
Provided by: PubMed Central
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