Review
Brain nicotinic acetylcholine receptors: native subtypes and their relevance

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Neuronal nicotinic acetylcholine receptors comprise a heterogeneous class of cationic channels that is present throughout the nervous system. These channels are involved both in physiological functions (including cognition, reward, motor activity and analgesia) and in pathological conditions such as Alzheimer's disease, Parkinson's disease, some forms of epilepsy, depression, autism and schizophrenia. They are also the targets of tobacco-smoking effects and addiction. Neuronal nicotinic acetylcholine receptors are pentamers of homomeric or heteromeric combinations of α (α2–α10) and β (β2–β4) subunits, which have different pharmacological and biophysical properties and locations in the brain. The lack of subtype-specific ligands and the fact that many neuronal cells express multiple subtypes initially hampered the identification of the different native nicotinic acetylcholine receptor subtypes, but the increasing knowledge of subtype composition and roles will be of considerable interest for the development of new and clinically useful nicotinic acetylcholine receptor ligands.

Introduction

Ionotropic neuronal nicotinic acetylcholine receptors are heterogeneous cationic channels that are widely distributed in both the nervous system and non-neuronal tissues, and their opening is controlled by the endogenous neurotransmitter acetylcholine (ACh) or exogenous ligands such as nicotine. They consist of homopentameric or heteropentameric subtypes that are present in various regions of the CNS; they are principally located at presynaptic or preterminal sites (where they modulate neurotransmitter release), and are sometimes found on cell bodies or dendrites (where they mediate postsynaptic effects) 1, 2, 3.

In the CNS, acetylcholine-mediated innervation acting through nicotinic acetylcholine receptors regulates processes such as transmitter release, cell excitability and neuronal integration, which are crucial for network operations and influence physiological functions such as arousal, sleep, fatigue, anxiety, the central processing of pain, food intake and several cognitive functions 1, 2, 4. Nicotinic acetylcholine receptors are particularly important in two crucial periods of brain life: early pre- and perinatal circuit formation, and age-related cell degeneration. They are involved in neuronal survival because nicotinic agonists have been shown to be neuroprotective in both in vivo and in vitro models (reviewed in Ref. [5]). Furthermore, it is becoming evident that the perturbation of nicotinic acetylcholine neurotransmission can lead to various diseases during development, adulthood and aging.

Several comprehensive reviews have described the structure and function of these channels 2, 3, 4, 6, 7, 8, 9, 10, 11, 12. We therefore aim to provide a short overview of recent studies of the subunit composition, function and pharmacology of native nicotinic acetylcholine receptor subtypes.

Section snippets

Receptor subtype composition and ligand-binding sites

Neuronal nicotinic acetylcholine receptors form a heterogeneous family of subtypes (Figure 1) formed by five subunits arranged around a central pore that is permeable to cations. These subunits are encoded by nine α (α2–α10) and three β (β2–β4) subunit genes, which are expressed in the nervous system and in several non-neuronal tissues 2, 4, 7(Figure 1a). Two main subfamilies of neuronal nicotinic acetylcholine receptors subtypes have been identified so far: αbungarotoxin (αBgtx)-sensitive and

Critique of methods for identifying receptor subtype expression

The identification of nicotinic acetylcholine receptor subtype composition is currently based on a combination of technical approaches and the availability of nicotinic acetylcholine receptor subunit knockout or knock-in mice. Any revision of the three generally accepted compositional rules listed above (e.g. a different receptor stoichiometry with three ‘true’ α subunits and two non-α subunits, see above) would require our current deductions concerning receptor composition to be changed (see

Native subtypes

In defining the native subtypes of nicotinic acetylcholine receptor, we will follow the rules and caveats described above. Table 1 and Figure 1 show the composition, localization and number of native subtypes identified in different brain regions of the animal species studied so far. The subtypes are identified by the list of their subunits.

Involvement of native subtypes in pathological states

Studies of receptor subunit knockout mice have shown that brain nicotinic acetylcholine receptors are not essential for survival or for the execution of basic behaviors [2]. They are, however, important for the fine control of several more sophisticated and complex behaviors that can be evaluated only by means of appropriate tests or in particularly labile situations such as the aged brain. These findings place nicotinic acetylcholine receptors in a different, and perhaps more important,

Concluding remarks

The functional data obtained from heterologous systems show that a simple one- or two-subunit nicotinic acetylcholine receptor would be sufficient to assure a nicotinic response to a target cell, but studies of various tissues indicate that native nicotinic acetylcholine receptors often contain more than one type of α or β subunit, and can consist of up to four different subunits. Thus, the number of biologically relevant receptor subtypes (with their distinct biophysical and pharmacological

Acknowledgements

We apologize to the many authors whose original contributions have not been cited owing to space restrictions. We thank Milena Moretti for help with identifying the subtypes, and Annalisa Gaimarri and Loredana Riganti for help with the figures. This work was supported by grants from the Italian PRIN (2005054943 to F.C. and M.Z.), the Fondazione Cariplo (2004/1419 to F.C.); and the Italian FIRB (RBNE01RHZM to C.G.).

References (88)

  • L. Azam

    α-Conotoxin BuIA, a novel peptide from Conus bullatus, distinguishes among neuronal nicotinic acetylcholine receptors

    J. Biol. Chem.

    (2005)
  • L.J. Cook

    Candidate gene association studies of the α4 (CHRNA4) and β2 (CHRNB2) neuronal nicotinic acetylcholine receptor subunit genes in Alzheimer's disease

    Neurosci. Lett.

    (2004)
  • J. Sallette

    Nicotine upregulates its own receptors through enhanced intracellular maturation

    Neuron

    (2005)
  • Y. Xiao

    Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells

    Bioorg. Med. Chem. Lett.

    (2004)
  • S.J. Rousseau

    Presynaptic α7 and non-α7 nicotinic acetylcholine receptors modulate [3H]d-aspartate release from rat frontal cortex in vitro

    Neuropharmacology

    (2005)
  • M. Loffler

    Dopamine release in human neocortical slices: characterization of inhibitory autoreceptors and of nicotinic acetylcholine receptor-evoked release

    Brain Res. Bull.

    (2006)
  • Y.J. Cao

    Different nicotinic acetylcholine receptor subtypes mediating striatal and prefrontal cortical [3H]dopamine release

    Neuropharmacology

    (2005)
  • K.T. O’Leary et al.

    Enhanced nicotinic acetylcholine receptor-mediated [3H]norepinephrine release from neonatal rat hypothalamus

    Neuropharmacology

    (2006)
  • P.R. Sanberg

    Nicotine for the treatment of Tourette's syndrome

    Pharmacol. Ther.

    (1997)
  • M.F. Poirier

    Prevalence of smoking in psychiatric patients

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2002)
  • C.M. Martin-Ruiz

    Molecular analysis of nicotinic receptor expression in autism

    Brain Res. Mol. Brain Res.

    (2004)
  • C.R. Breese

    Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia

    Neuropsychopharmacology

    (2000)
  • C.M. Martin-Ruiz

    Dementia rating and nicotinic receptor expression in the prefrontal cortex in schizophrenia

    Biol. Psychiatry

    (2003)
  • M. Quik

    Smoking, nicotine and Parkinson's disease

    Trends Neurosci.

    (2004)
  • L. Burghaus

    Loss of nicotinic acetylcholine receptor subunits α4 and α7 in the cerebral cortex of Parkinson patients

    Parkinsonism Relat. Disord.

    (2003)
  • J.A. Court

    Nicotine binding in human striatum: elevation in schizophrenia and reductions in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease and in relation to neuroleptic medication

    Neuroscience

    (2000)
  • J. Court

    Nicotinic receptor abnormalities in Alzheimer's disease

    Biol. Psychiatry

    (2001)
  • R.C. Hogg

    Nicotinic acetylcholine receptors: from structure to brain function

    Rev. Physiol. Biochem. Pharmacol.

    (2003)
  • R.C. Hogg et al.

    Nicotinic acetylcholine receptors as drug targets

    Curr. Drug Targets CNS Neurol. Disord.

    (2004)
  • M.R. Picciotto et al.

    Nicotinic receptors in aging and dementia

    J. Neurobiol.

    (2002)
  • N. Le Novere

    The diversity of subunit composition in ChRs: evolutionary origins, physiologic and pharmacologic consequences

    J. Neurobiol.

    (2002)
  • 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)
  • J. Drago

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

    Cell. Mol. Life Sci.

    (2003)
  • E. Sher

    Physiological roles of neuronal nicotinic receptor subtypes: new insights on the nicotinic modulation of neurotransmitter release, synaptic transmission and plasticity

    Curr. Top. Med. Chem.

    (2004)
  • A.A. Jensen

    Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations

    J. Med. Chem.

    (2005)
  • J.P. Changeux et al.

    Allosteric mechanisms of signal transduction

    Science

    (2005)
  • S.B. Hansen

    Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations

    EMBO J.

    (2005)
  • P.J. Corringer

    Nicotinic receptors at the amino acid level

    Annu. Rev. Pharmacol. Toxicol.

    (2000)
  • M.E. Nelson

    Alternate stoichiometries of α4β2 nicotinic acetylcholine receptors

    Mol. Pharmacol.

    (2003)
  • M. Moretti

    Nicotinic acetylcholine receptor subtypes expression during rat retina development and their regulation by visual experience

    Mol. Pharmacol.

    (2004)
  • N. Le Novere

    Neuronal nicotinic receptor α6 subunit mRNA is selectively concentrated in catecholaminergic nuclei of the rat brain

    Eur. J. Neurosci.

    (1996)
  • L. Azam

    Expression of neuronal nicotinic acetylcholine receptor subunit mRNAs within midbrain dopamine neurons

    J. Comp. Neurol.

    (2002)
  • R. Klink

    Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei

    J. Neurosci.

    (2001)
  • P. Whiteaker

    Involvement of the α3 subunit in central nicotinic binding populations

    J. Neurosci.

    (2002)
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