It has been 25 years since the identification of two proteins that facilitate communication between nerve cells — a significant achievement that revealed a group of related proteins. In recognition of this advancement, The Journal of Biological Chemistry has published a series of articles that assess what we know about each family member in this group and where that research is headed.
This superfamily was recognized in 1987 with the discoveries of the genes that encode two of its members, the GABAA and glycine receptors, and of the similarity of these proteins to the first characterized family of this group, the nicotinic acetylcholine receptors. F. Anne Stephenson of the University College London School of Pharmacy, an author on one of the two 1987 articles, explains that these findings, in addition to revealing the new superfamily, led to the discovery of multiple protein subtypes within each family. Since that time, two additional protein families have been added to the group — the serotonin-3 receptors and the glutamate-gated chloride ion channels.
Proteins in this group, known as the cys-loop ligand-gated ion channel superfamily, are targeted by neurotransmitters to allow the passage of ions across cell membranes, ultimately affecting functions such as muscle contraction, anxiety, pain, vision, and food digestion and passage. For example, mutations in GABAA receptor subunits are involved in some forms of epilepsy. Also, certain antianxiety drugs target these receptors, and drugs that affect serotonin-3 receptors treat irritable bowel syndrome and the nausea and vomiting associated with chemotherapy.
The JBC series chronicles the history of this field, highlighting the many advances that scientists have made over the past 25 years. Each review focuses on a different member of the group, covering its structure, regulation and functions. The roles of some of these proteins in diseases and therapeutics are also discussed.
Jean-Pierre Changeux reviews nicotinic acetylcholine receptors in “The nicotinic acetylcholine receptor: the founding father of the pentameric ligand-gated ion channel superfamily.” The nicotinic acetylcholine receptor was the first neurotransmitter receptor identified, and Changeux discusses the major breakthroughs that led to the achievement — the acquisition of single cells from the electric organ of the electric eel, advances in membrane fragment purification, the discovery of toxins that bound to the receptor and could be used with affinity chromatography to purify the receptor, the preparation of membranes from the electric ray that were rich in the receptor, and the investigation of the receptor’s structure by electron microscopy. The author also reviews the receptor subunits, acetylcholine binding sites, the channel opening mechanism and binding sites for regulatory molecules.
Erwin Sigel and Michael Steinmann focus on GABAA receptors in “Structure, function and modulation of GABAA receptors.” The review emphasizes the complexity of GABAA receptors, which are formed by five subunits that enclose a chloride ion channel. For example, the authors note that 19 subunit isoforms exist, with expression patterns varying broadly — some are extensively expressed in the central nervous system, and others are limited to specific cell types or tissues. Additionally, the authors discuss GABAA regulation through post-translational modification, receptor associated proteins, endogenous compounds and exogenous small molecules. The authors conclude with a discussion of topics for future research.
Sébastien Dutertre, Cord-Michael Becker and Heinrich Betz cover glycine receptors in “Inhibitory glycine receptors: an update.” The authors discuss the structure of glycine receptors and their subunits and the binding sites of agonists, antagonists and allosteric modulators. They also review the various isoforms of glycine receptors, which differ in expression in embryos and adults. Many mutations of glycine receptors lead to hyperekplexia (commonly called startle disease), and the authors discuss the role of some of these mutations in preventing proper glycine signaling.
Adrian Wolstenholme discusses glutamate-gated chloride channels — receptors that are similar to mammalian glycine receptors but that are unique to protostome invertebrates. The author describes the structure of these receptors — noting that this was the first eukaryotic ligand-gated anion channel for which a three-dimensional structure was determined — and reviews the roles of these receptors, such as regulating movement, feeding and sensory information. The review highlights the economic and therapeutic significance of these receptors, which are targets of certain pesticides and of parasite-removing drugs.
Sarah Lummis reviews serotonin-3 receptors, starting with the discovery of this receptor family. The author discusses the receptor structure and the five known receptor subunits. The review also explains how serotonin-3 receptors function and the roles that these receptors play, for example, in regulating intestinal movement. While there are currently serotonin-3 targeting drugs for the treatment of conditions such as irritable bowel syndrome and chemotherapy-induced nausea, the author notes that further understanding of receptor subunits C through E may lead to treatment for a variety of diseases, such as migraines, bulimia and psychosis.
Since 1987, scientists have overcome major challenges and learned where particular protein subtypes of a family are located and what functions they perform. Stephenson emphasizes that the advancements in this field were a boost for the pharmaceutical industry in terms of finding selective drugs that lack undesirable side effects, such as nonsedating antianxiety drugs, which act on a particular subtype of GABAA receptors.
The JBC series was convened by Stephenson, who today is an associate editor of the journal and whose lab continues to investigate the structures and functions of neurotransmitter receptors, including the GABAA receptors, in health and disease.
Danielle Gutierrez (email@example.com) is a freelance science writer based in Corpus Christi, Texas.