Discuss the extent to which nicotinic acetylcholine receptors are considered important targets for drug therapy and discovery.
Acetylcholine receptors are of two types: Nicotinic and muscarinic receptors. In this essay we will focus on nicotinic acetylcholine receptors and some of the drugs that work on this receptor, which either lead to or cure a disease.
Nicotinic acetylcholine receptors (nAChRs) are cholinergic receptors that are of three main subtypes:
1. The muscle receptors those are located at skeletal neuromuscular junctions,
2. Ganglionic receptors in the PNS (Peripheral Nervous System) and the brain,
3. CNS (Central Nervous System) type receptors, which are located across the brain.
These receptors act as ligand gated ion channels (LGICs) which are a member of the cys-loop family and are pentameric structures (Neal L. Benowitz, 1996). Ligand gated ion channels are oligomeric proteins that contain a central ion channel pore. They are structurally sub-divided into distinct sub families, where the subunit structures differ as the subunits can either be homomeric or heteromeric. Each subunit has four transmembrane domains and the agonist binding sites are at the subunit interfaces, being the channel pore. In muscles, the subunits of the receptors differ, as they may either be in the embryonic form (α12β1δγ) or the adult form (α12β1δε). Similarly the subunits differ slightly in the ganglion and CNS receptors, therefore the muscle receptors and neuronal receptors differ in their pharmacological properties apart from molecular structure.
Nicotinic acetylcholine receptors are activated by binding of chemical messengers to the binding site. These messengers may be neurotransmitters such as acetylcholine (ACh), ligands such as nicotine or other synthetic molecules. Acetylcholine is one drug that acts on all the nicotinic receptor types, but has no clinical uses.
When an agonist binds to the receptor, the subunits undergo a conformational change, which in turn opens the channel pore allowing the flow of ions (eg. Na+, K+, Ca2+) along their electrochemical gradient ie. either into or out of the cell. This binding stabilises the open and desensitised states of the receptors. Binding of a ligand to the receptor mediates a fast response, therefore stimulating the pores to open instantly and remain open till the ligand diffuses away from the receptor. This usually takes about one millisecond. The consequence of an agonist binding to a nicotinic acetylcholine receptor results in depolarisation of the membrane, hence they are excitatory receptors.
Stimulation of the muscle receptors found in the neuromuscular junctions (mainly postsynaptic) causes muscle contraction or relaxation. Examples of some agonists that work on muscle type receptors are acetylcholine, carbachol and succinylcholine (suxamethonium). Tubocurarines, pancuronium, α-Bungarotoxin, on the other hand are examples of antagonists that work on muscle type receptors. Examples of some ganglionic receptor type agonists are nicotine, lobeline. Some antagonists of this receptor are trimetaphan and hexamethonium. Epibatidine, nicotine, dimethylphenypiperazinium are some agonists that act on the CNS type receptors and mecamylamine and α-Bungarotoxin are a few of the CNS type receptor antagonists. Actions and clinical uses of some of these drugs are explained below.
Suxamethonium imitates the actions of acetylcholine and acts as a depolarizing neuromuscular blocker. It is used clinically as a muscle relaxant during anaesthesia and is popularly used in emergency medicine; as was about 50 years ago, due to its relatively fast onset and short duration of action (Jonsson M., Dabrowski M., et al, 2006). Suxamethonium first produces a twitch (fasciculation) as the end plate depolarises, causing excitation of muscle fibres. Tubocurarine and pancuronium are competitive antagonists and act as transmission blockers at the neuromuscular junction. Tubocurarine is now rarely used clinically, whereas pancuronium is widely used as a muscle relaxant in anaesthesia. Unlike suxamethonium, pancuronium is a non-depolarising agent, thereby no depolarisation of the membrane, which therefore produces no muscle contraction upon binding with the nicotinic receptor.
Myasthenia gravis is an autoimmune disorder that causes a loss of nAChRs from the neuromuscular junction. It is a neuromuscular disease, where individuals show signs of muscle weakness and fatigue resulting from a failure in neuromuscular transmission. This failure in transmission is caused due to circulating antibodies blocking the neuromuscular junction, preventing the stimulation of the nicotinic receptors by binding with acetylcholine. It is medically treated with anticholinesterases, e.g. neostigmine or immunosuppressant drugs, e.g. azathioprine. Neostigmine indirectly stimulates the nicotinic receptors. It blocks the breakdown of acetylcholine, by inhibiting the active site of acetylcholinesterase before ACh can reach the postsynaptic terminal, thereby prolonging the firing of an action potential in the postganglionic muscle fibres. In myasthenia gravis, using anticholinesterases will allow ACh to bind to the few receptors available, causing muscle contraction.
Nicotine is a pharmacologically active compound (alkaloid) found in tobacco plants. It acts in the peripheral nervous system (autonomic ganglia) as well as the central nervous system. In small doses, nicotine acts as a stimulant and in larger doses it blocks ganglia. It's main and common form of intake by humans is by cigarette smoking. Stimulation of the ganglionic receptors produces various responses of the autonomic reflex (peripheral effects), such as, tachycardia, increase in blood pressure and cardiac output, reduction in gastrointestinal motility and sweating. All these effects reduce in response with repeated dosage. Apart from activating the receptors, nicotine also causes desensitisation, which plays an important role in its effects, as after continuous exposure to drug, the effects of a dose of nicotine are diminished in animals (Rang & Dale et al, 2007). This thereby causes drug tolerance and eventually dependence. Chain smoking occurs due to nicotine addiction and smoking can lead to many diseases such as lung disease.
Nicotine activates the nicotinic receptors found in the adrenal medulla which stimulates the release of adrenaline (Neal L. Benowitz, 1996). Nicotine addiction appears to be linked to dopamine release, particularly in the nigrostriatal region (Neal L. Benowitz, 1996). Dopamine forms part of a reward pathway system, which as mentioned above plays a key role in drug dependence. Dopamine acts presynaptically as well as postsynaptically. Most of the effects of nicotine though are widely expressed across the CNS, particularly the cortex and hippocampus in the brain (Rang & Dale et al, 2007).
Nicotine also has clinical uses. It is currently available as a gum, a nasal spray, skin patches, which are used for smoking cessation. “Nicotine is also being investigated for therapy of Alzheimer's disease, Parkinson's disease, Tourette's syndrome, sleep apnea and attention deficit disorder”, as stated by Neal L. Benowitz, 1996.
In the brain, the α7-nAChRs play a role in cognitive function and are located at glutamatergic terminals of the ventral tegmental area (VTA), from which mesolimbic dopaminergic neurons project. Alzheimer's disease (AD) is a disease of mood and cognition where memory and communication become disrupted. “The loss of cholinergic neurones in the hippocampus and frontal cortex is a feature of this disease”, stated by Rang & Dale et al, 2007. Cholinesterase inhibitors (anticholinesterases), for example, Tacrine (the first drug approved) or donepezil are used to treat AD, with the latter being more effective in improving quality of life (Rang & Dale et al, 2007). According to G. Sharma and S, Vijayaraghavan, more recent studies show and suggest nAChR agonists and antagonists would make better and more effective therapeutic approaches to this disease. In Alzheimer's disease nicotine has been shown to improve memory deficits (Sharma, G.;Vijayaraghavan, S., 2008).
Schizophrenia is a disorder of mood and thought processes that involves increased dopamine function. Patients therefore have hallucinations and become delirious, thereby resulting in paranoia and suspicions. Treatment is by using antipsychotic drugs that work at the alpha-7 receptors in the brain. A correlation was found between schizophrenia and smoking, where people with schizophrenia had more than three times the number of cigarettes to the general population (SfN, 2008). This led scientists to believe nicotine had therapeutic effects on the CNS, normalising some deficits involves with this disorder. Therefore smoking cigarettes represented a form of self medication in schizophrenics.
The nicotinic receptor, α7-receptor is proving to be a major target for drug development of neurodegenerative diseases such as schizophrenia, Alzheimer's and Parkinson's disease. Data from structure and function of nAChRs, how they work and metabolism of nicotine, all propose probable sites of interest for drug design.
1. Rang & Dale et al. (2007) Pharmacology, 6th edition.
2. Malin Jonsson, M.D.,* Michael Dabrowski, Ph.D.,† David A. Gurley, M.S.,‡ Olof Larsson, Ph.D.,§ Edwin C. Johnson, Ph.D.,‡ Bertil B. Fredholm, M.D., Ph.D.,_ Lars I. Eriksson, M.D., Ph.D.#: Activation and Inhibition of Human Muscular and Neuronal Nicotinic Acetylcholine Receptors by Succinylcholine. J. Anesthesiology 2006; 104:724-33
3. Sharma, G.1;Vijayaraghavan, S.: Nicotinic Receptors Containing the α7 Subunit: A Model for Rational Drug Design. Current Medicinal Chemistry, Volume 15,Issue 28, December 2008 , pp. 2921-2932(12)
4. (SfN) Smoking and Schizophrenia, Society for Neuroscience, Brain Briefings, January 2008. http://www.sfn.org/index.aspx?pagename=brainBriefings_smoking