Nicotinic Acetylcholine Receptors in Health and Disease
Our studies have involved basic scientific research about structure and function of nicotinic acetylcholine receptors, which is essential if we are to know how they are involved in health and disease and how they might be targeted therapeutically. Much of that work has involved studies of drugs that affect nicotinic receptors in various ways and that are leads for therapeutic intervention. Because subtle changes in nervous system or receptor properties can have profound behavioral and health or disease impact, some of our work also illuminates how numbers and function of receptors are regulated normally or in disease conditions.
Our work has contributed to the realization not only that there are a number of nicotinic receptor subtypes, which can be selectively targeted, but also a multitude of other biological entities that can have similar influences on receptor activity.
As just a few examples of the clinical relevance of these nicotinic receptors, their numbers are decreased in Parkinson’s and Alzheimer’s diseases, and we have mechanistic evidence for their involvement early and perhaps causally in these neurodegenerative disorders. This opens possibilities of targeting nicotinic receptors for drug therapies to slow or stop disease progression, especially given promising innovations that allow disease detection in the decades before memory loss or movement disorders become clinically evident rather than too late in disease progression for useful intervention.
Nicotinic receptors are involved in neuromuscular disorders, having been identified as targets for autoimmune responses or gene mutations causing myasthenia gravis and located in the dystrophin-related complex targeted in muscular dystrophy. Recent indications that mutations in nicotinic receptor building blocks rival those of other mutations implicated in amyotropic lateral sclerosis, Lou Gehrig’s disease.
Whether in these disorders or other neurodegenerative conditions such as Alzheimer’s disease, nicotinic receptor involvement in neurodegeneration may mimic developmentally relevant “programmed neuronal death” that occurs naturally to control, for example, numbers of motor neurons. Common to these phenomena is natural or aberrant overactivity in nicotinic receptors, which, when created in mutant mice or in human neuronal cell cultures, is lethal to neurons.
Mutations in nicotinic receptors are associated with certain inherited forms of epilepsy. We have identified reasons why these mutations might cause the excessive electrical activity seen in epilepsy and other seizure disorders. Nicotinic acetylcholine receptors act as ion channels, embedded in the neuronal cell exterior membrane surface. Electrical activity of these receptors occurs when they interact with acetylcholine, causing opening of the ion channel that is closed at rest. If channels stay open too much or for too long, electrical activity can become abnormally excessive and harmful in nerve cells.
We have shown that some epilepsy-related mutations in nicotinic receptors cause—even when measuring openings of single channels—prolongation of channel open times or open probabilities.
Our work has helped to show that nicotinic receptors are expressed widely throughout the body, with some receptors subtypes being richly expressed in immune system cells. The immune system evolved much earlier than did nervous systems, and so it should come as no surprise that the phylogenetically most-ancient nicotinic receptor family members are not in the healthy brain at all but are in the immune system.
In our studies of mouse models of some forms of multiple sclerosis, we have found that disease onset and severity involves harmful activity of one of these receptor subtypes. We think that we can target that family member to tamp down inflammatory and autoimmune responses that cause multiple sclerosis or other disorders. Another nicotinic receptor subtype seems to play roles protecting the brain and spinal cord in the multiple sclerosis model, offering another potential therapeutic target. Perhaps most exciting is our finding that there is no recovery from disease when another nicotinic receptor subtype is absent.
Diseases such as multiple sclerosis progress even if treatment or natural phenomena lower brain inflammation because of the loss of myelin, the material that creates “insulation” of neuronal “wires,” leading to short-circuiting in the disease. Myelin loss occurs because it and the specialized cells that make myelin are attacked by a misguided immune system. Recovery in multiple sclerosis requires restoration of those specialized cells so that new myelin can be made again. No cure for multiple sclerosis can occur unless there are these restorative processes. We think that nicotinic receptors are involved in replenishment of specialized myelin-producing cells, that their loss accounts for lack of recovery, and that we can target them therapeutically to effect useful treatment and perhaps recovery in multiple sclerosis.
Collaborations with Barrow investigators have allowed us to inform how inflammatory processes and nicotinic receptors are involved in hemorrhagic or ischemic strokes and in vascular malformations, sometimes involving nicotinic receptors on vascular complexes but also nicotinic receptors in the immune system.
Metastatic brain tumors occur more frequently than tumors that start in the brain, but some intriguing recent findings indicate that some nicotinic receptor building blocks not found in the healthy brain appear at high levels in certain forms of brain-specific tumors. At a minimum, this affords possible use of those receptors as biomarkers indicating the presence of tumor and responses to therapy, but these observations suggest that much more work is needed to understand why these changes occur and what they mean for tumor development.
Repeating a theme mentioned above, roles of immune system conversation with the brain in development or treatment of brain tumors, and actions of nicotinic receptor signaling across the immune and nervous systems in that conversation, might afford therapeutic options.
Affecting 10 times more individuals in the United States than those afflicted, for example, with Alzheimer’s disease (see Chart 1), is nicotine dependence. Nicotine dependence is the ultimate cause of all tobacco-related diseases. Our work has helped to advance hypotheses that tobacco use represents a form of nicotine self-medication, which develops in some individuals to correct chemical and electrical signaling deficits associated with emotional difficulties, cognitive difficulties, or both.
Indeed, individuals with mental health problems, including depression, anxiety, and attention deficit disorder, are at higher risk of developing nicotine dependence. This has been underscored by studies showing that children having those issues have such elevated risk, not that use of tobacco products causes those issues, as was thought to be the case 70 years ago. About 40% of the mentally ill, including as many as 90% of schizophrenics, are smokers.
More recently, individual genetic variations in some receptors have been associated with heightened susceptibility to nicotine dependence and to lung cancer. Our work has helped to inspire clinicians to provide true “nicotine replacement” in smoking cessation programs and to recognize that they need to identify and treat not just nicotine dependence, but also the underlying neuropsychiatric conditions that lead to nicotine self-medication, if we are to end use of tobacco products. Note that roles for nicotine itself, aside from dependence on it, in tobacco-related diseases remains unclear. This is in sharp contrast the clearly harmful effects of many of the other estimated 4,000 compounds in tobacco, which nearly double when tobacco is combusted, including known carcinogens, let alone inhalation of carbon monoxide. Serious and rational scientific evidence also is required to ensure that alternative products for nicotine delivery also are not harmful, as revealed by the observation that other constituents in nicotine vaping devices are culprits causing deadly respiratory consequences.
Our studies have helped to identify what we call “a neurochemical endpoint” for nicotine dependence. It is a reduction in function of certain receptor subtypes upon sustained exposure to human smoker levels of nicotine. Our work also has shown that useful aids to smoking cessation also have the same effect, taking the brain to the same neurochemical endpoint. Those observations have allowed us to help identify, sometimes in work supported via National Drug Discovery and Development Cooperative Group awards or industry collaborations, novel drugs that have superior preclinical features than smoking cessation products in the marketplace. Not by coincidence, we also have found that some drugs that are antidepressants target nicotinic receptors, and we have identified new compounds designed to act at nicotinic receptors that are superior in preclinical studies to antidepressants in the marketplace.
Drug codependence also is evident, in that upwards of 90% of alcoholics smoke. Nicotinic receptors are targets of much pharmaceutical research, in part because nicotine itself has the ability to improve attention and cognition in Parkinson’s, Alzheimer’s, or attention deficit disorder subjects; improve mood in depressed individuals; and reduce the frequency of ticks in Tourette’s patients. However, there are times in life, especially in perinatal periods and during adolescence and young adulthood, when abnormal signaling through nicotinic receptors mediated by nicotine can have harmful influences on many of the body’s organ systems.
Nicotinic acetylcholine receptors also have been implicated in a host of other medical conditions (see Chart 1). Already mentioned are anxiety, depression, alcoholism, and less common disorders such as Alzheimer’s disease, epilepsy, stroke, etc. But arthritis (afflicting over 100 million Americans), nearly as prevalent obesity, sleep and GI disorders, lung disorders, and chronic pain (nicotine was employed since ancient times as a potent analgesic) are even more common than nicotine dependence (and likely overlap with it).
Diabetes and even tinnitus appear to involve nicotinic receptors, pathogenically and perhaps as therapeutic targets, perhaps in part because nicotinic receptors play important roles in the birth of neurons, in their ability to form synaptic connections between nerve cells and nerve or other cell targets in virtually all organ systems, and in their roles in continued maintenance of those connections.