ReviewRegulation of neuronal nicotinic receptor traffic and expression
Introduction
Neurones communicate with each other at highly specialised contact sites “called synapses” which consist of a pre-synaptic nerve terminal and a post-synaptic neuron. Synaptic transmission is fundamental to many brain processes and its strength can be enhanced or diminished by cell activity. This plasticity depends on mechanisms that regulate the strength of synaptic transmission at the levels, inter alia, of neurotransmitter release from synaptic terminals and the concentration of neurotransmitter receptors in post-synaptic neurones.
Different lines of evidence indicate that both plasma membrane domains and matrix-bound receptor-associated proteins are crucial for the localisation and anchoring of receptors in the pre- and post-synaptic membrane of central synapses. It has been found that various receptors and enzymes associate with cytosolic and cytoskeletal proteins, via PDZ-domain protein–protein interactions, which not only allow the recruitment of ionotropic and metabotropic receptors at the synapse, but also the assembly of signalling cascades and enzyme complexes at synaptic sites.
Receptor localisation and trafficking in neurones are thus fundamental mechanisms involved in synaptic plasticity, the pathophysiology of diseases and drug activities. Receptors trafficking refers to their translocation from the endoplasmic reticulum (ER) to a plasma membrane domain, to their internalisation from plasma membrane to different cytoplasmic compartments and finally the lateral movements that regulate and control receptor aggregation at synaptic and extrasynaptic sites (Green and Millar, 1995, Kittler and Moss, 2001).
Receptor traffic is particularly complex in the case of ligand-gated ion channels, consisting of multimeric proteins formed by different subunits, because very strict quality control is required in the early steps of subunit assembly with appropriate subunit pairing in order to ensure that functional receptors can reach the surface membrane (Green and Millar, 1995).
In the nervous system, the neurotransmitter acetylcholine (ACh) binds to metabotropic muscarinic and ionotropic nicotinic receptors (nAChRs), interactions that are recognised as being highly relevant to several functions including cognition, locomotion and analgesia (Champtiaux and Changeux, 2002, Drago et al., 2003, Picciotto et al., 2000, Picciotto et al., 2001). In particular, the interactions of ACh with nAChRs have recently been reevaluated. nAChRs in the CNS are mainly located pre-synaptically and modulate the release of almost all neurotransmitters, but they have a post-synaptic localisation in some areas, where they mediate fast synaptic transmission (Dajas-Bailador and Wonnacott, 2004, Gotti and Clementi, 2004, Jensen et al., 2005).
nAChRs are also the targets of nicotine (the most common drug of abuse) whose complex activities in the nervous system are due to its ability to mimic the activity of ACh on this receptor subset. The different effects of nicotine are determined by the functional features and location of the nAChR subtypes with which it interacts in specific neuronal systems (Gentry and Lukas, 2002, Laviolette and van der Kooy, 2004).
This review will summarise recent data concerning nAChR subtypes expressed in the CNS, and how they are regulated by chronic nicotine administration and nicotinic drug treatment.
Section snippets
Structure of nAChRs
Ionotropic neuronal nAChRs are a very heterogeneous class of receptor subtypes consisting of the combinations of different subunits encoded by distinct genes. The genes that have been cloned so far are divided into two subfamilies of nine α (α2–α10) and three β (β2–β4) subunits and are expressed in the nervous system, cochlea and a number of non-neuronal tissues (Gotti and Clementi, 2004, Hogg et al., 2003).
The topology of the receptor subunits consists of a large extracellular N-terminus
Nicotine regulation of nicotinic receptor subtypes
One generally accepted paradigm in cell membrane receptor studies is that the over-stimulation induced by agonists leads to a reduction in the number of cell surface receptors, whereas the prolonged inactivation induced by antagonists has the opposite effect (Gentry and Lukas, 2002). However, studies of the brains of tobacco smokers and animals chronically exposed to nicotine have shown that nAChRs apparently escape from these general rules because long-term exposure to nicotine often triggers
Up-regulation of nAChRs by a novel nicotinic antagonist
Most of our knowledge of nAChR up-regulation comes from studies of the effects of nicotine on the α4β2 subtype, whereas much less is known about the effect of nicotine and nicotinic drugs on other subtypes. We have recently compared the effects of chronic treatment with nicotine or the novel cholinergic drug 1,2-bis-N-cytisinylethane (CC4) in SH-SY5Y neuroblastoma cells (which natively express both α3⁎ and α7⁎ AChRs and resemble human sympathetic neurones); and the “controls” were primary
Acknowledgments
We thank Prof Michele Zoli for critically reading of the manuscript.
This work was supported by the Italian PRIN 2005054943 (F. Clementi), Fondazione Cariplo grant No. 2004/1419 to F. Clementi; and FIRB (RBNE01RHZM) 2003 grant to C. Gotti.
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The three authors contributed equally to this work.