Activation of neuronal nicotinic receptors inhibits acetylcholine
release in the neuromuscular junction by increasing Ca2+ flux through
Cav1 channels
Abstract
Background and Purpose: Cholinergic neurotransmission is a key signal
pathway in the peripheral nervous system (PNS) and in several branches
of the central nervous system (CNS). Despite the fact that it has been
studied extensively for a long period of time, some aspects of its
regulation still have not yet been established. One is relationship
between nicotine-induced autoregulation of acetylcholine (ACh) release
with changes in the concentration of presynaptic calcium levels.
Experimental Approach: The mouse neuromuscular junction of m. Levator
Auris Longus was chosen as the model of the cholinergic synapse. ACh
release was assessed by electrophysiological methods. Changes in the
calcium transients were recorded using a calcium-sensitive dye.
Functional interaction between nicotinic ACh receptors and calcium
channels was investigated pharmacologically using specific agonists and
antagonists. Key Results: Nicotine hydrogen tartrate salt (considered as
a stable form for potential therapeutic delivery of nicotine) effects on
the parameters of ACh release from the nerve ending were analyzed.
Nicotine application (10 μM) decrease the amount of evoked ACh release,
while calcium transient increase in the motor nerve terminal. Both of
these effects of nicotine were abolished by the neuronal ACh receptor
antagonist dihydro-beta-erythroidine and Cav1 blockers, verapamil and
nitrendipine. Conclusion and Implications: Neuronal nicotinic ACh
receptors activation decreases the number of ACh quanta released by
boosting calcium influx through Cav1 channels. Understanding of
mechanisms of autoregulation of ACh release is important for the
searching new approaches treat diseases associated with cholinergic
dysfunction.