Chapter One - Neuronal Nicotinic Acetylcholine Receptor Structure and Function and Response to Nicotine
Introduction
Mammalian nicotinic acetylcholine receptors (nAChRs) are composed on five subunits arranged around a water-filled pore (Fig. 1). The neuronal subunits are divided into the alpha (α2–α7, α9, and α10) and beta (β2–β4) classifications based on the presence of adjacent cysteine groups in the extracellular domain of only the α subunits (Albuquerque et al., 2009, Dani and Balfour, 2011, Dani and Bertrand, 2007, Fasoli and Gotti, 2015, Lewis and Picciotto, 2013, McGehee and Role, 1995, McKay et al., 2007, Papke, 2014, Unwin, 2013, Zoli et al., 2014). The α8 subunit has been found in avian tissue but not in mammalian tissue. Much of the structural and functional diversity of neuronal nAChRs arises from the many possible subunit combinations. The two most commonly found nAChR subtypes in the mammalian brain are the α4β2 heteromeric and the α7 homomeric subunit combinations, which are didactically represented in Fig. 1 showing their agonist-binding sites.
The α4β2 is a subtype with high affinity for nicotine, and the α7 subtype is the main contributor to the α-bungarotoxin-binding sites of the brain. Because each subunit has sidedness and is not completely symmetrical, the placement of the many different subunits within the pentameric complex can produce thousands of different nAChR subtypes. For example, the α5 subunit may combine as an “accessory” subunit that does not contribute to the agonist-binding site (Fig. 1, right), but its presence modifies the functional properties of the receptor/channel complex. Another complicating feature is illustrated by considering the α4β2 heteromeric receptor that can exist as a 2(α4)–3(β2) receptor (represented in Fig. 1, left). It also can exist as a 3(α4)–2(β2) receptor, which can potentially have another agonist-binding site arising from the sidedness of the α subunit (Fasoli & Gotti, 2015). Therefore, each different pentameric complex can, in principle, produce a nAChR receptor/channel with different functional characteristics: e.g., opening, closing, and desensitizing kinetics; ionic conductance; cationic selectivity; and pharmacological properties. In practice, however, these subtypes commonly share many structural and functional properties, leading to the grouping of nAChRs into a few main neuronal nAChR subtype classifications. For example, those that contain the α7 subunit (α7*) as a homomeric or heteromeric receptor most commonly also have accompanying characteristics. They bind α-bungarotoxin, have relatively low affinity for nicotine and have relatively fast kinetics. Those that contain β2 (β2*) commonly have high affinity for nicotine, desensitize to low agonist concentrations, have relatively slow kinetics, and do not bind α-bungarotoxin. Because these broad nAChR categories include such a diverse collection of subtypes, not all the members perfectly follow these broad functional characteristics.
Other nAChR subtypes have a much more restricted distribution in the brain, but in some cases they can constitute the most abundant receptor subtype in a restricted brain area where they are expressed. For example, α3β4* nAChRs, which are commonly found in the peripheral nervous system, are expressed at high levels only in the medial habenula, interpeduncular nucleus, and locus coeruleus. α3β4* nAChRs have low affinity for nicotine and have much slower desensitization kinetics than α4β2 nAChRs (Fenster, Rains, Noerager, Quick, & Lester, 1997).
All the mammalian neuronal nAChR subtypes do share the general functional property of being permeable to small monovalent and divalent cations. The main conducting species under biological conditions are Na+, K+, and Ca2 +. Agonists, such as endogenous acetylcholine (ACh) or exogenous nicotine (which can be obtained from smoking tobacco), stabilize the open conformation of the nAChR channel that transiently permeates small cations for several milliseconds before closing back to a resting state or closing to a desensitized state that is unresponsive to agonists. Brief exposure to high concentrations of the neurotransmitter, such as acetylcholine at a synaptic cleft, favors synchronous opening of the nAChRs’ pores. However, prolonged expose to low concentrations of nicotine, as obtained from tobacco use, produces some activation but also significant desensitization of nAChRs to the unresponsive closed state (Dani et al., 2000, Giniatullin et al., 2005, Quick and Lester, 2002, Wooltorton et al., 2003).
Section snippets
Nicotinic Receptor Structure
The neuronal nAChR subunits share a similar linear structure and transmembrane topology with the muscle α1 subunit (Fig. 2A) (Papke, 2014). The relatively long extracellular N-terminal domain contributes to ligand binding, followed by the three hydrophobic transmembrane regions (M1–M3), a large intracellular loop, a fourth transmembrane region (M4), and ultimately a short extracellular C-terminus (Fig. 2A). The general hydrophobicity plot for the alpha subunits suggests the basic structural
Nicotinic Receptor Channel Gating
In most cases, there are two ACh-binding sites per muscle and heteromeric neuronal nAChR. Each binding site is formed by a pocket at the interface between adjacent subunits within the extracellular N-terminal domain (Albuquerque et al., 2009, Galzi et al., 1990, Karlin, 2002, Papke, 2014, Sine, 2002, Sine and Engel, 2006, Unwin, 2013). The situation is more complicated for the homomeric α7 nAChR subtype, where the sidedness of the interfaces between the alpha subunits provides five
Cationic Permeability of the Nicotinic Receptor Pore
Mammalian nAChRs are cation selective, being permeable to small monovalent and divalent cations that can fit through the narrowest hydrophilic region of the open pore (Albuquerque et al., 2009, Dani, 1989, Dani and Bertrand, 2007, Dani and Eisenman, 1987). When the linear sequences of homologous cationic nAChR and anionic channel domains are aligned, a proline residue in the anionic channel is found to be missing from the short intracellular segment between M1 and M2 of the nAChRs (as
Nicotinic Receptor Response to Nicotine from Tobacco
Tobacco smoking activates and desensitizes nAChRs as 20–100 nM nicotine (Brody et al., 2006, Rose et al., 1999) reaches throughout the brain (Dani, Kosten, & Benowitz, 2014). Although many areas of the brain participate, nicotinic receptors of the midbrain dopamine (DA) area are particularly important during the initiation of the addiction process (Dani et al., 2014, De Biasi and Dani, 2011). On the midbrain DA and GABA neurons’ cell bodies and postsynaptically, many of the nAChRs contain α4β2
Conclusion
Nicotinic receptors of the brain share a basic fundamental property: they mediate a cationic conductance upon binding agonist. The tremendous diversity of nAChR subtypes provides the structural and functional flexibility necessary for them to play multiple, varied roles (Zoli et al., 2014). Broad, sparse cholinergic projects throughout the brain ensure that nicotinic mechanisms modulate the neuronal excitability of relatively wide circuits (Albuquerque et al., 2009, Dani and Bertrand, 2007).
Acknowledgment
Research in the laboratory and effort for this review was supported by the following NIH grants: NIDA DA09411 and NINDS NS21229.
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