Review
Allosteric mechanisms in normal and pathological nicotinic acetylcholine receptors

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Abstract

Recent chemical and advanced structural studies on site-directed and naturally occurring pathological mutants of individual members of the multigene family of nicotinic acetylcholine receptors have yielded structure–function relationships supporting indirect ‘allosteric’ interactions between the acetylcholine-binding sites and the ion channel in signal transduction.

Introduction

Membrane receptors for transmitters, peptides and pharmacological agents are central to signal transduction. They selectively recognize chemical effectors (neuronal or hormonal) and transduce, in an ‘indirect’ allosteric manner [1], binding recognition into biological action though the activation of ligand-gated ion channels (LGICs) and/or G-protein-coupled receptors (GPCRs). Since their initial isolation and characterization in the early 1970s as integral membrane proteins, about 2000 different receptor species have been cloned and sequenced. In the C. elegans genome, for example, there are up to 90 LGIC genes, and about 5% of all C. elegans genes encode a GPCR, including about 1000 orphan receptors that may be chemoreceptors [2]. Many of these receptor genes are conserved through evolution [3]. About 5% of the known human genes are assigned to receptors, which are the targets of major drugs, and are responsible for several important human pathologies.

In this review, we discuss new insights gained in the much studied model provided by the nicotinic acetylcholine receptor (nAChR), and in addition make reference to recent observations made in other systems concerning general receptor mechanisms.

With respect to neurotransmitter signaling, the classical example of the neuromuscular junction—where ACh is liberated in less than 0.2ms as a high local concentration pulse (up to 10−3M) over a postsynaptic dense layer of nAChR molecules—may not be as general as initially thought. Acetylcholine, as well as other neurotransmitters and peptides, may be released in a volume or paracrine mode [4] at the level of varicosities, thus modulating, in a ‘tonic’ manner, a widely dispersed population of high-affinity receptors. For example, in the spinal cord, endogenous ACh tonically modulates serotonin release, in part through nAChRs present on inhibitory γ-amino butyric acid (GABA)ergic neurons [5].

Section snippets

Subunit composition and distribution of neuronal nAChR

Nicotinic acetylcholine receptors exist as ‘homopentamers’ made up of α7, α8 or α9 subunits, or ‘heteropentamers’ comprising various combinations of α2–α6 with β2–β4 subunits, α9 with α10 subunits, or precisely arranged (α1)2–β1–γ/ε–δ subunits in muscle. (For the latest findings, see articles in the special issues of Eur J Pharmacol 393:1-320 [2000], and Neuropharmacology 39:2515-2855 [2000], as well as the Soc Neurosci Abstr [2000].)

New subunit combinations have been discovered recently by

Structure–function relations updated

Our current understanding of the nAChR molecule is based mainly on chemical and genetic approaches combined with predictive methods and the limited structural information available. The success in determining the three-dimensional structure of the binding region of a glutamate receptor 28., 29•.—with the details largely anticipated by models based on homologies with bacterial periplasmic binding proteins [30]—underlies the predictive capacities of secondary structure computations from first

Modes and models of signal transduction

Single nAChR molecules respond to ACh by undergoing a conformational transition to an open-channel state, associated with slower ‘modulatory’ transitions to (or from) desensitized states. These properties are readily described by an allosteric model (see Fig. 2a) that is based on concerted transitions between pre-existing conformational states (implying a mechanism involving ‘rigid body motion’) [1]. Nevertheless, because of their simplicity, standard sequential models of two ACh bindings

nAChR allosteric mutations, deletions and pathological ‘states of consciousness’

Natural mutations in the human population are continuing to provide a rich source of complex and surprising phenotypes, particularly in congenital myasthenic syndromes, for which over 50 distinct mutations have been characterized, with most occurring in the ε subunit gene [72]. Roughly half of the well-characterized mutants fall into the category of ‘gain-of-function’ or ‘hyperactive’ phenotypes, argued above as supporting the allosteric scheme 50., 51.. Moreover, in-frame duplication of six

Long-term regulation

Considerable attention has been focused recently on the phenomenon of nAChR upregulation, initially in relation to the effects of smoking [91]. Current research has used prolonged exposure to agonists for various human nAChR subunits 92., 93., 94.. Some evidence suggests that this phenomenon may be related to desensitization for α4β2 receptors in oocytes [95], although in other studies on α4β2 receptors in M10 cells upregulation occurred at concentrations of agonist 1–2 orders of magnitude

Conclusions and future prospects

Considerable progress has been made in establishing the stereochemical basis of ligand-binding and ion channel properties for nAChR in general and for the individual variations among members of the multigene family. A fairly coherent picture is emerging on the basis of algorithms for prediction of conformation [31••], medium-resolution structural studies [43••], and astute use of site-directed mutagenesis [32]. In addition, studies on the three-dimensional structure of a soluble molluscan

Update

Evidence has been presented for narrowing of the channel involving residues above the M1–M2 loop in the desensitized state [104]. An article describing studies on mice with an α4 channel mutation reported in abstract form [90] has now been published [105]. Progress in analyzing the mode of α7 inhibition by the β-amyloid peptide has been reported by two groups 106., 107.. Upregulation has now been shown to involve conductance changes in the case of α4β2 receptors in K-177 cells [108]. Concerning

Acknowledgements

We thank Pierre Jean Corringer for helpful comments. This work was supported by the Collège de France, the Université de Genève, the Centre National de la Recherche Scientifique, the Association Française contre les Myopathies, the Association pour la Recherche sur le Cancer and the Commission of the European Communities.

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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