Muscle and neuronal nicotinic acetylcholine receptors

Abstract

Nicotinic acetylcholine receptors (nAChRs) are integral membrane proteins and prototypic members of the ligand-gated ion-channel superfamily, which has precursors in the prokaryotic world. They are formed by the assembly of five transmembrane subunits, selected from a pool of 17 homologous polypeptides (a1-10, b1-4, c, d, and e). There are many nAChR subtypes, each consisting of a specific combination of subunits, which mediate diverse physiological functions. They are widely expressed in the central nervous system, while, in the periphery, they mediate synaptic transmission at the neuromuscular junction and ganglia. nAChRs are also found in non-neuronal ⁄ nonmuscle cells (keratinocytes, epithelia, macrophages, etc.). Extensive research has determined the specific function of several nAChR subtypes. nAChRs are now important therapeutic targets for various diseases, including myasthenia gravis, Alzheimer's and Parkinson's diseases, and schizophrenia, as well as for the cessation of smoking. However, knowledge is still incomplete, largely because of a lack of high-resolution X-ray structures for these molecules. Nevertheless, electron microscopy studies on 2D crystals of nAChR from fish electric organs and the determination of the high-resolution X-ray structure of the acetylcholine binding protein (AChBP) from snails, a homolog of the extracellular domain of the nAChR, have been major steps forward and the data obtained have important implications for the design of subtype-specific drugs. Here, we review some of the latest advances in our understanding of nAChRs and their involvement in physiology and pathology.

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

“…[18][19][20] In contrast to nicotinic neuromuscular junction receptors, which are composed of a1-, b1-, g-, d-and e-subunits, neuronal nAChRs are composed of a-or b-subunit only. They may be heteropentamers composed of combinations of a-and b-subunits in different ratios or homopentamers of asubunits.…”

“…' The predominant nAChR in the human brain, a4b2*, has high affinity for nicotine, but differences in the a4/b2-subunits ratio can lead to subtypes with different pharmacological and functional properties. 19,26 The brain nAChRs are activated by endogenous (acetylcholine) and exogenous ligands (nicotine).…”

“…Importantly, the receptors are highly sensitive to modulation by many molecules, including divalent cations, steroids, protein kinases and more. 19,22,34 The brain nAChRs change considerably during the development and aging in all species 22,25 and are involved in the pathophysiology of several central nervous system (CNS) diseases other than nicotine addiction. Mutations in the channel region of a4-or b2-subunits have been described in families suffering from autosomal dominant frontal lobe epilepsy, 22 and rare microdeletions of the 15q13.3 segment, which includes the CHRNA7 gene, were reported recently in idiopathic generalized epilepsy.…”

“…21 As presynaptic receptors, nAChRs modulate exocytosis and neurotransmitter release either by activation of voltage-operated calcium channels following membrane depolarization, or directly because of calcium influx through the receptor pore, altering the intracellular calcium concentration. 19 The a4b2* receptors (the predominant receptor subtype in the brain of humans and other mammalian species) and homomeric a7-receptors are widely expressed within the CNS, 47 while the expression pattern of other subunits is much more restricted to particular brain regions. 18,25,20 a3b4* is the major receptor in the autonomic nervous system and adrenal medulla.…”

The invertebrate pharmacology of insecticides acting at nicotinic acetylcholine receptors

“…14,15) The vertebrate nAChRs possess up to five binding sites lying at the interface between an α-subunit and either another α-subunit in its homopentameric form or a different α or complementary β-subunit in its heteropentameric form. [16][17][18] A similar arrangement for the agonist binding site in the invertebrate nAChR is also postulated, although the exact subunit composition of functional insect nAChRs remains unknown. 19) Unlike verterbrate nAChRs, heterologous expression of genuine heteropentameric (α and β subunit combinations) insect nAChRs has not been successful, although heteropentameric receptors composed of mixed α subunits has been achieved.…”