Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function

Abstract

The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a “receptive substance,” from which the idea of a “receptor” came to light. Subsequent studies aided by the Torpedo electric organ, a rich source of muscle-type nicotinic receptors (nAChRs), and the discovery of α-bungarotoxin, a snake toxin that binds pseudo-irreversibly to the muscle nAChR, resulted in the muscle nAChR being the best characterized ligand-gated ion channel hitherto. With the advancement of functional and genetic studies in the late 1980s, the existence of nAChRs in the mammalian brain was confirmed and the realization that the numerous nAChR subtypes contribute to the psychoactive properties of nicotine and other drugs of abuse and to the neuropathology of various diseases, including Alzheimer’s, Parkinson’s, and schizophrenia, has since emerged. This review provides a comprehensive overview of these findings and the more recent revelations of the impact that the rich diversity in function and expression of this receptor family has on neuronal and nonneuronal cells throughout the body. Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy.

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

“…Thus, the extracellular levels of KYNA attained in the present study were in the low-to-mid-nanomolar range, sufficient to inhibit a7nAChRs (Hilmas et al, 2001) but less likely to reach the concentrations required to inhibit NMDARs directly (Kessler et al, 1989;Parsons et al, 1997). In the hippocampus as elsewhere (Albuquerque et al, 2009), a7nAChRs are prominently associated with nerve terminals, where they can be targeted to modulate glutamate release (Fabian-Fine et al, 2001;Gray et al, 1996;Lagostena et al, 2008). a7nAChR agonists enhance, whereas a7nAChR antagonists reduce, the release of glutamate into the extracellular compartment (Barik and Wonnacott, 2006).…”

[3H]Epibatidine Photolabels Non-equivalent Amino Acids in the Agonist Binding Site of Torpedo and α4β2 Nicotinic Acetylcholine Receptors

“…Nicotinic acetylcholine receptors (nAChRs) 3 are prototypical members of the Cys loop superfamily of neurotransmittergated ion channels that mediate the actions of the neurotransmitter acetylcholine (1). nAChRs from vertebrate skeletal muscle and the electric organs of Torpedo rays are heteropentamers of homologous subunits with a stoichiometry of 2␣:␤: ␥(⑀):␦ that are arranged pseudosymmetrically around central cation-selective ion channels (1,2).…”

“…nAChRs from vertebrate skeletal muscle and the electric organs of Torpedo rays are heteropentamers of homologous subunits with a stoichiometry of 2␣:␤: ␥(⑀):␦ that are arranged pseudosymmetrically around central cation-selective ion channels (1,2). There are 12 mammalian neuronal nAChR subunit genes: nine neuronal ␣ subunits (␣2-␣10) and three neuronal ␤ subunits (␤2-␤4).…”

Duplicated copy of CHRNA7 increases risk and worsens prognosis of COPD and lung cancer

“…CHRNA7 is one of the most predominant nAChRs expressed in both central nervous system and pulmonary tissue, [24][25][26] and is responsible for mediating the effects of nicotine addict and toxicological effect caused by nicotine metabolites, such as nicotine-derived nitrosamine ketone (NNK). [27][28][29] CHRNA7 may play a role in the pathogenesis of COPD and lung cancer because of its effect on nicotine addiction.…”