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    Nicotinic Acetylcholine Receptors in Health and Disease

    Chemical Signaling

    Chemical signaling between nerve cells and their targets occurs in anatomically specialized areas called synapses. When an electrical impulse reaches the terminus of a nerve cell axon, balloon-like synaptic vesicles inside the cell filled with chemical neurotransmitters fuse with the plasma membrane at the axon terminal. This fusion at one point creates an omega structure. As synaptic vesicles explode into the extracellular space, they release neurotransmitters. These chemical messengers then cross the narrow synaptic cleft.

    Some neurotransmitters dock at binding sites on a structurally matched neurotransmitter receptor. These receptors are located in the plasma membrane of the target cell. This membrane consists of 2-sided bed of phospholipids with polar heads facing the inside or outside of the cell, linked in the middle of the membrane by interactions between their hydrophobic tails. At rest, the channel at the center of each receptor is closed. The plasma membrane is impermeable to sodium (Na+), potassium (K+), or calcium ions (Ca2+), and the target cell is electrically silent. However, when enough neurotransmitters dock at binding sites, the shape of the neurotransmitter receptor changes, causing the channel to widen and allowing ions to flow through the channel. If enough sodium ions flow inward, electrical activity in the target cell is triggered. If there is adequate electrical activity, an electrical impulse is propagated in the target cells, and the entire process repeats itself. Outward flow of positively charged potassium ions flowing through specialized channels neutralizes electrical activity in the cell, returning it to the resting state. The inward flow of calcium ions can have many effects on signaling within the cell.

    Acetylcholine is the natural chemical neurotransmitter made by many nerve cells. Nicotine from tobacco has many of the same effects as acetylcholine. Both acetylcholine and nicotine exert their effects on the nervous system by acting on nicotinic acetylcholine receptors, which are sodium (and calcium) ion-permeable neurotransmitter receptors that function as acetylcholine- or nicotine-gated ion channels.

    Neurotoxins

    Some neurotoxins have the potential to act on nicotinic acetylcholine receptors. For example, neurotoxic proteins found in the venom of poisonous snakes such as cobras (illustrated here), kraits, mambas, and sea snakes target nicotinic receptors in mammalian muscle and some nicotinic receptors in the nervous system. These toxins literally cover up the acetylcholine or nicotine binding sites on receptors, preventing acetylcholine or nicotine from triggering the ion channel to open.

    In the wild, when such toxins are delivered to a mammal, they diffuse to the diaphragm. Once there, they block nicotinic receptors that receive chemical signals from the phrenic nerve that would normally promote breathing. The prey is immobilized and eventually dies from asphyxiation. In a laboratory setting, these toxins are valuable tools for the study of nicotinic receptors.

    Other toxins (e.g. from frogs, algae, or sea snails) also can be used to study nicotinic receptors. In fact, nicotine itself is a toxic substance and seems to have evolved as a natural insecticide.

    The wide distribution and critical physiological roles of nicotinic acetylcholine receptors make them ideal targets in the attempt to modify brain and body functions pharmacologically. Not surprisingly, nicotinic receptors are targeted by a variety of toxins and bioactive substances. Consequently, these receptors are the subject of intensive investigations that seek to identify new medicines for use in treating neurological and/or psychiatric disorders, along with other diseases that strike outside the nervous system.

    Nicotine

    Both nicotine and acetylcholine act on nicotinic acetylcholine receptors. Acetylcholine is a naturally occurring neurotransmitter used by many nerve cells to send chemical signals to their targets. Nicotine is a biologically active component of tobacco. These two molecules have additional structural nuances in three dimensions that are not evident in two dimensions.

    One face of the acetylcholine molecule has a structure that is mimicked by that of one face of the nicotine molecule. This analogous face of each molecule is recognized by nicotinic acetylcholine receptors.

    Another face of the acetylcholine molecule has a structure that is mimicked by muscarine, a chemical obtained from a particular type of mushroom. Acetylcholine and muscarine can act on other kinds of neurotransmitter receptors, called muscarinic acetylcholine receptors. Muscarinic receptors have functions and structures quite distinct from those of nicotinic receptors. It is fascinating that nature has used one chemical, acetylcholine, in the signaling of two strikingly different kinds of receptors.

    For more information about nicotine receptors, visit The Ligand Gated Ion Channel Database.

    Subunits

    Subunits are the building blocks of nicotinic acetylcholine receptors (nAChR). Nicotinic acetylcholine receptors are neurotransmitter-gated ion channels. Opening of the channel is triggered by the presence of nicotine or acetylcholine and allows positively charged ions to flow down their concentration gradients across the plasma membrane.

    Nicotinic acetylcholine receptors exist as diverse subtypes expressed in different tissues or cells. For example, nicotinic receptors in adult mammalian muscle are different from two types of receptors in autonomic neurons and from the predominant types of receptors in the brain. Each distinct nicotinic receptor subtype is composed of different combinations of genetically distinct subunits. The subunits themselves are made up of transmembrane proteins, and it is thought that a complete nicotinic receptor is composed of five subunits. Subunits assemble in a fashion similar to the staves or planks of a wooden barrel to create a central empty space—the ion channel.

    Evolutionary and protein sequence relationships between nicotinic receptor subunits from different species are known (see Lukas, 1998, and Lukas et al., 1999, for details). The most closely related subunits include alpha4 and alpha2, alpha6 and alpha3, and beta2 and beta3. The most ancient subunits (e.g., alpha7) also form the simplest types of receptors constructed from a single type of subunit.

    Genetic variations of the nicotinic receptor subunits exist across individuals and are known, in some cases, to contribute to or to cause neurological diseases. It is also possible that they could influence individual behavior, such as susceptibility to use of tobacco products.

    For more information about nicotine receptors, visit The Ligand Gated Ion Channel Database.

    About Barrow

    Since our doors opened as a regional specialty center in 1962, we have grown into one of the premiere destinations in the world for neurology and neurosurgery. Our experienced, highly skilled, and comprehensive team of neurological specialists can provide you with a complete spectrum of care–from diagnosis through outpatient neurorehabilitation–under one roof. Barrow Neurological Institute: Discover. Educate. Heal.