Regulation of neuronal nicotinic receptor traffic and expression

doi:10.1016/j.brainresrev.2007.02.005

Brain Research Reviews

Volume 55, Issue 1, August 2007, Pages 134-143

https://doi.org/10.1016/j.brainresrev.2007.02.005 Get rights and content

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) are a family of cation channels widely distributed in the brain, whose subunit composition and biophysical properties vary depending on the subtype and the area of the brain in which they are found. Brain nAChRs are also the target of nicotine, the most widespread drug of abuse. Chronic nicotine exposure differentially affects the number, subunit composition, stoichiometry and functional state of some nAChR subtypes, leaving others substantially unaffected. In this review, we will summarise recent data concerning the nAChR subtypes expressed in the CNS, and how they are regulated by means of chronic nicotine and/or nicotinic drugs. We will particularly focus on the possible mechanisms involved in the up-regulation of nAChRs.

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.

References (72)

C.C. Boido et al.
Cytisine derivatives as ligands for neuronal nicotine receptors and with various pharmacological activities
Farmaco
(2003)
C. Canu Boido et al.
Synthesis and preliminary pharmacological evaluation of some cytisine derivatives
Farmaco
(1999)
E. Carbonnelle et al.
Nitrogen substitution modifies the activity of cytisine on neuronal nicotinic receptor subtypes
Eur. J. Pharmacol.
(2003)
P.H. Celie et al.
Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures
Neuron
(2004)
J.P. Changeux et al.
Allosteric receptors after 30 years
Neuron
(1998)
F. Dajas-Bailador et al.
Nicotinic acetylcholine receptors and the regulation of neuronal signalling
Trends Pharmacol. Sci.
(2004)
T. Darsow et al.
Exocytic trafficking is required for nicotine-induced up-regulation of alpha 4 beta 2 nicotinic acetylcholine receptors
J. Biol. Chem.
(2005)
M.B. Ficklin et al.
Ubiquilin-1 regulates nicotine-induced up-regulation of neuronal nicotinic acetylcholine receptors
J. Biol. Chem.
(2005)
S. Fucile
Ca²⁺ permeability of nicotinic acetylcholine receptors
Cell Calcium
(2004)
C. Gotti et al.
Neuronal nicotinic receptors: from structure to pathology
Prog. Neurobiol.
(2004)

C. Gotti et al.

Brain nicotinic acetylcholine receptors: native subtypes and their relevance

Trends Pharmacol. Sci.

(2006)

W.N. Green et al.

Ion-channel assembly

Trends Neurosci.

(1995)

S. Halevi et al.

Conservation within the RIC-3 gene family. Effectors of mammalian nicotinic acetylcholine receptor expression

J. Biol. Chem.

(2003)

E.M. Jeanclos et al.

The chaperone protein 14-3-3eta interacts with the nicotinic acetylcholine receptor alpha 4 subunit. Evidence for a dynamic role in subunit stabilization

J. Biol. Chem.

(2001)

L. Lin et al.

The calcium sensor protein visinin-like protein-1 modulates the surface expression and agonist sensitivity of the alpha 4beta 2 nicotinic acetylcholine receptor

J. Biol. Chem.

(2002)

M.J. Marks et al.

Subsets of acetylcholine-stimulated 86Rb+ efflux and [125I]-epibatidine binding sites in C57BL/6 mouse brain are differentially affected by chronic nicotine treatment

Neuropharmacology

(2004)

M. Mugnaini et al.

Selective down-regulation of [(125)I]Y0-alpha-conotoxin MII binding in rat mesostriatal dopamine pathway following continuous infusion of nicotine

Neuroscience

(2006)

E. Palma et al.

Nicotinic acetylcholine receptors assembled from the alpha7 and beta3 subunits

J. Biol. Chem.

(1999)

M.R. Picciotto

Nicotine as a modulator of behavior: beyond the inverted U

Trends Pharmacol. Sci.

(2003)

M.R. Picciotto et al.

Nicotinic receptors in the brain. Links between molecular biology and behavior

Neuropsychopharmacology

(2000)

M.R. Picciotto et al.

Neuronal nicotinic acetylcholine receptor subunit knockout mice: physiological and behavioral phenotypes and possible clinical implications

Pharmacol. Ther.

(2001)

J. Sallette et al.

An extracellular protein microdomain controls up-regulation of neuronal nicotinic acetylcholine receptors by nicotine

J. Biol. Chem.

(2004)

J. Sallette et al.

Nicotine upregulates its own receptors through enhanced intracellular maturation

Neuron

(2005)

M. Villarroya et al.

Synthesis and pharmacology of alkanediguanidinium compounds that block the neuronal nicotinic acetylcholine receptor

Bioorg. Med. Chem.

(1996)

F. Wang et al.

Chronic nicotine treatment up-regulates human alpha3 beta2 but not alpha3 beta4 acetylcholine receptors stably transfected in human embryonic kidney cells

J. Biol. Chem.

(1998)

M.E. Williams et al.

Ric-3 promotes functional expression of the nicotinic acetylcholine receptor alpha7 subunit in mammalian cells

J. Biol. Chem.

(2005)

S. Broadbent et al.

Incorporation of the beta3 subunit has a dominant-negative effect on the function of recombinant central-type neuronal nicotinic receptors

Mol. Pharmacol.

(2006)

B. Buisson et al.

Chronic exposure to nicotine upregulates the human (alpha)4(beta)2 nicotinic acetylcholine receptor function

J. Neurosci.

(2001)

N. Champtiaux et al.

Knock-out and knock-in mice to investigate the role of nicotinic receptors in the central nervous system

Curr. Drug Targets. CNS Neurol. Disord.

(2002)

N. Champtiaux et al.

Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice

J. Neurosci.

(2003)

L.E. Chavez-Noriega et al.

Pharmacological characterization of recombinant human neuronal nicotinic acetylcholine receptors h alpha 2 beta 2, h alpha 2 beta 4, h alpha 3 beta 2, h alpha 3 beta 4, h alpha 4 beta 2, h alpha 4 beta 4 and h alpha 7 expressed in Xenopus oocytes

J. Pharmacol. Exp. Ther.

(1997)

P.J. Corringer et al.

Nicotinic receptors at the amino acid level

Annu. Rev. Pharmacol. Toxicol.

(2000)

J. Drago et al.

Neuronal nicotinic receptors: insights gained from gene knockout and knockin mutant mice

Cell. Mol. Life Sci.

(2003)

C.L. Gentry et al.

Regulation of nicotinic acetylcholine receptor numbers and function by chronic nicotine exposure

Curr. Drug Targets. CNS Neurol. Disord.

(2002)

C. Gotti et al.

Expression of nigrostriatal alpha 6-containing nicotinic acetylcholine receptors is selectively reduced, but not eliminated, by beta 3 subunit gene deletion

Mol. Pharmacol.

(2005)

M. Grilli et al.

Chronic nicotine differentially affects the function of nicotinic receptor subtypes regulating neurotransmitter release

J. Neurochem.

(2005)

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¹: The three authors contributed equally to this work.

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ReviewRegulation of neuronal nicotinic receptor traffic and expression

Abstract

Introduction

Section snippets

Structure of nAChRs

Nicotine regulation of nicotinic receptor subtypes

Up-regulation of nAChRs by a novel nicotinic antagonist

Acknowledgments

Farmaco

Farmaco

Eur. J. Pharmacol.

Neuron

Neuron

Trends Pharmacol. Sci.

J. Biol. Chem.

J. Biol. Chem.

Cell Calcium

Prog. Neurobiol.

Trends Pharmacol. Sci.

Trends Neurosci.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Neuropharmacology

Neuroscience

J. Biol. Chem.

Trends Pharmacol. Sci.

Neuropsychopharmacology

Pharmacol. Ther.

J. Biol. Chem.

Neuron

Bioorg. Med. Chem.

J. Biol. Chem.

J. Biol. Chem.

Incorporation of the beta3 subunit has a dominant-negative effect on the function of recombinant central-type neuronal nicotinic receptors

Mol. Pharmacol.

Chronic exposure to nicotine upregulates the human (alpha)4(beta)2 nicotinic acetylcholine receptor function

J. Neurosci.

Knock-out and knock-in mice to investigate the role of nicotinic receptors in the central nervous system

Curr. Drug Targets. CNS Neurol. Disord.

Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice

J. Neurosci.

Pharmacological characterization of recombinant human neuronal nicotinic acetylcholine receptors h alpha 2 beta 2, h alpha 2 beta 4, h alpha 3 beta 2, h alpha 3 beta 4, h alpha 4 beta 2, h alpha 4 beta 4 and h alpha 7 expressed in Xenopus oocytes

J. Pharmacol. Exp. Ther.

Nicotinic receptors at the amino acid level

Annu. Rev. Pharmacol. Toxicol.

Neuronal nicotinic receptors: insights gained from gene knockout and knockin mutant mice

Cell. Mol. Life Sci.

Regulation of nicotinic acetylcholine receptor numbers and function by chronic nicotine exposure

Curr. Drug Targets. CNS Neurol. Disord.

Expression of nigrostriatal alpha 6-containing nicotinic acetylcholine receptors is selectively reduced, but not eliminated, by beta 3 subunit gene deletion

Mol. Pharmacol.

Chronic nicotine differentially affects the function of nicotinic receptor subtypes regulating neurotransmitter release

J. Neurochem.

Review
Regulation of neuronal nicotinic receptor traffic and expression