The Nicotinic Acetylcholine Receptor: The Founding Father of the Pentameric Ligand-gated Ion Channel Superfamily

Abstract

A critical event in the history of biological chemistry was the chemical identification of the first neurotransmitter receptor, the nicotinic acetylcholine receptor. Disciplines as diverse as electrophysiology, pharmacology, and biochemistry joined together in a unified and rational manner with the common goal of successfully identifying the molecular device that converts a chemical signal into an electrical one in the nervous system. The nicotinic receptor has become the founding father of a broad family of pentameric membrane receptors, paving the way for their identification, including that of the GABA A receptors.It has been 42 years since the isolation of the nicotinic acetylcholine receptor (nAChR) 2 from fish electric organ, the first ligand-gated ion channel and the first ion channel ever identified; 25 years since the first GABA A and glycine receptor subunits were cloned and sequenced and concomitantly their homology with the nAChRs recognized; and 5 years since the discovery that closely homologous ligand-gated ion channels are present in prokaryotes (1). In this minireview, I briefly retrace the main steps in the discovery of the nAChR, the titular head of this receptor superfamily. The Concept of Receptor and the Chemical Identification of the Acetylcholine ReceptorThe English physiologist John Newport Langley, working with neuromuscular preparations, proposed in 1905 that muscle tissue possesses "a substance that combines with nicotine and curare . . . receives the stimulus and transmits it." He called the muscle entity the "receptive substance." In the subsequent 50 years, the concept of pharmacological receptors inspired three main lines of research: first, the pharmacological approach aimed at characterizing the specificity of the receptor site by using novel chemical ligands (e.g. the distinction between nicotinic and muscarinic AChRs by Sir Henry Dale); second, the electrophysiological approach exemplified by Bernard Katz and John Eccles aimed at understanding the ionic responses to endogenous neurotransmitter signals; and third, the chemical tradition aimed at the chemical identification of the receptor molecule(s).In the late 1960s, lipids, polysaccharides, proteins, and even nucleic acids were considered as potential receptors. The early independent efforts of Carlos Chagas, Eduardo de Robertis, and David Nachmansohn to identify the receptor for acetylcholine (ACh) in the electric organ of the fish Electrophorus electricus with radioactive ligands were abandoned because their tissue extracts lacked specificity (2). However, in the course of these studies, Nachmansohn recognized the extraordinarily rich content of nicotinic synapses in the electric organ (2). With Ernest Schoffeniels, he devised a method for preparing individual cells, or electroplaques, from the electric organ. This offered the opportunity to investigate, simultaneously, the electrophysiological, pharmacological, and biochemical characteristics of the response to ACh within the same biological system (2). At this time, th...

Studies on an Acetylcholine Binding Protein Identify a Basic Residue in Loop G on theβ1 Strand as a New Structural Determinant of Neonicotinoid Actions

“…Nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop superfamily of ligand-gated ion channels, and neuronal nAChRs play a central role in fast cholinergic neurotransmission in both vertebrates and invertebrates (Changeux, 2012;Hurst et al, 2013). nAChRs are composed of five subunit proteins and form a pentagonal assembly.…”

A single amino acid polymorphism in the Drosophila melanogaster Dα1 (ALS) subunit enhances neonicotinoid efficacy at Dα1-chicken β2 hybrid nicotinic acetylcholine receptor expressed in Xenopus laevis oocytes

“…27) This could provide an explanation for the higher efficacy of clothianidin compared to imidacloprid because clothianidin can form a hydrogen bond at its NH with the backbone carbonyl of a tryptophan in loop B, 19) which is not seen in the nAChR-imidacloprid complex, and thus gate the channel more effectively than imidacloprid even in the twist state. Also, in Changeux's proposed gating mechanism, the stronger the interactions with Trp139, the stronger would be the interactions with the Trp170 in loop B, accounting for the higher efficacy of neonicotinoids on the Leu108-type than in the His108-type Dα1β2 nAChR.…”

Concomitant alpha7 and beta2 nicotinic AChR subunit deficiency leads to impaired energy homeostasis and increased physical activity in mice

“…nAChRs are formed by the symmetrical arrangement of five subunits around a central pore [1,2], resulting in many combinations since in mammals 16 nAChR subunits composing heteropentameric or homopentameric nAChRs have been discovered. The subunit composition of these receptors determines their expression pattern, function, and pharmacologic properties such as agonist sensitivity, desentizing period or ionic selectivity [3][4][5].…”