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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

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.

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