Trends in Pharmacological Sciences
ReviewBrain nicotinic acetylcholine receptors: native subtypes and their relevance
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.).
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