Abstract
Acetylcholine (ACh), an ubiquitous mediator substance broadly expressed in nature, acts as neurotransmitter in cholinergic synapses, generating specific communications with different time-courses. (1) Ultrafast transmission. Vertebrate neuromuscular junctions (NMJs) and nerve-electroplaque junctions (NEJs) are the fastest cholinergic synapses; able to transmit brief impulses (1–4 ms) at high frequencies. The collagen-tailed A12 acetylcholinesterase is concentrated in the synaptic cleft of NMJs and NEJs, were it curtails the postsynaptic response by ultrafast ACh hydrolysis. Here, additional processes contribute to make transmission so rapid. (2) Rapid transmission. At peripheral and central cholinergic neuro-neuronal synapses, transmission involves an initial, relatively rapid (10–50 ms) nicotinic response, followed by various muscarinic or nicotinic effects. Acetylcholinesterase (AChE) being not concentrated within these synapses, it does not curtail the initial rapid response. In contrast, the late responses are controlled by a globular form of AChE (mainly G4-AChE), which is membrane-bound and/or secreted. (3) Slow ACh signalling. In non-neuronal systems, in muscarinic domains, and in most regions of the central nervous system (CNS), many ACh-releasing structures (cells, axon terminals, varicosities, boutons) do not form true synaptic contacts, most muscarinic and also part of nicotinic receptors are extra-synaptic, often situated relatively far from ACh releasing spots. A12-AChE being virtually absent in CNS, G4-AChE is the most abundant form, whose function appears to modulate the “volume” transmission, keeping ACh concentration within limits in time and space.
Highlights
Acetylcholine (ACh) has been recognised as a neurotransmitter, initially in organs innervated by the parasympathetic nervous system [1], in neuromuscular junctions and in neuro-neuronal synapses of autonomic and central nervous systems [2,3]
Three features confer to A12-AChE its major role in the ultra-fast cholinergic transmission: (a) its location in the centre of the neuromuscular junctions (NMJs) junction, where it is positioned between the active zones of the motor nerve ending and the nicotinic receptors bound to the postsynaptic membrane boarding the primary cleft [15]; (b) its substrate inhibition for ACh concentrations exceeding 1 mM [28]; (c) its very high rate of ACh hydrolysis, beyond 103 ACh molecules/s [26,29]
The following complex responses are generated by slower, high-affinity, α4β2 nicotinic ACh receptors (nAChR), and by other mechanisms including currents mediated via glutamate receptors, since glutamate is co-released with ACh [80,89]
Summary
Acetylcholine (ACh) has been recognised as a neurotransmitter, initially in organs innervated by the parasympathetic nervous system [1], in neuromuscular junctions and in neuro-neuronal synapses of autonomic and central nervous systems [2,3]. Post-Synaptic Potential, EPSP), which is followed by a host of slower responses involving various types of muscarinic, nicotinic and other receptors In these synapses, acetylcholinesterase (AChE) is not concentrated in the narrow cleft separating pre- and postsynaptic membranes. A number of specialized features work together to shorten the flash-like impulses, enabling these junctions to fire at a very high frequency In this diversity of cholinergic mechanisms, time is a crucial parameter. The purpose of the present paper is to describe some cytological and molecular features which make a cholinergic cell to transmit messages with either a fast or a slow time course. G4-AChE is present in cholinergic and non-cholinergic neurons and glial cells (see review in [16]) These G4 molecules are predominantly amphiphilic as a result of their association with a proline-rich membrane anchor (PRiMA) [11,17]. Neurons and skeletal muscles both secrete large amounts of non-amphiphilic G4 molecules suggesting a specific physiological role for them [16,18,19,20]
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