The Nicotinic Acetylcholine Receptor - Essay Example

The nicotinic acetylcholine receptor Nicotinic acetylcholine receptors (nAChR) are proteins involved in the cell to cell communication in the nervous system. These are prototypical proteins that are located in the cell membrane that make it possible through the formation of ligand-gated ion channels across the surface of the cells and are responsible for diffusion of signals between cells (Kandel et al, 1995). The intercellular activity of this group of proteins plays a significant role in the brain function of the nervous system of mammals (Crick, 1994). The channels that these receptors formed are ionotropic or affected by ions of charges. Another property is the increase in opening of the neurotransmitter acetylcholine, similar to the muscarinic acetylcholine type, but compared to others this type can be activated by nicotine (Siegel et al., 1999; Itier and Bertrand, 2001). Being involved in the intercellular communication, these receptors are found in different parts of the body specifically in the central and peripheral nervous system. One of the functions of the nicotinic acetylcholine receptors is in connection with muscle contraction which is controlled by the peripheral nervous system (“Nicotinic acetylcholine receptors”, 2006). The performance of these receptors can be affected by chemical substances such as medicines and abused drugs. An example is the negative effect of cocaine and MK-801 [(+)dizocilpine], a medicine for convulsion to AChR (Hess et al, 2000). Studies of the receptors are being undertaken through the use of cryoelectron microscopy, mutagenesis and labelling. Results show that the structure that is involved in intercellular functions is the five twisted M2 alpha-helices surround a transmembrane (TM) pore (Sansom, 2000). The nicotinic receptors, in particular, have a molecular weight of approximately 280kDa. It belongs to the nicotinicoid receptor family which also has the 5 symmetrical receptor subunits arranged in a pore located in the centre. Members of this group of Cys-loop proteins include GABAA receptors, glycine receptors, and the type 3 serotonin receptors (Cascio, 2004; “Nicotinic acetylcholine receptors”, 2006). The structure of the nicotinic receptor is composed of twelve kinds of subunits with similar hydrophobic regions that form the pentamers, α2 to α10 and β2 to β4 (Siegel et al., 1999; Itier and Bertrand, 2001). Two α subunits, which is a combination of a β, a δ and either a γ or a ε comprise the muscle form of nAChR (Siegel et al., 1999; Itier and Bertrand, 2001; Giniatullin et al., 2005). On the other hand, the neuronal forms can be composed of different subunits (“Nicotinic acetylcholine receptors”, 2006). When the receptors work α subunits turn more symmetrical as the other subunits and pore approximately 0.65 nm opens. This takes place on the ACh binding site near the N termini of the molecule (Siegel et al., 1999; Colquhoun and Sivilotti, 2004; “Nicotinic acetylcholine receptors”, 2006). “The electrostatic isopotential surface--a surface representing constant electric potential--for a model of the nicotinic acetylcholine receptor. The model was developed by Igor Tsigelny, Naoya Sugiyama, and Palmer Taylor at the Departments of Pharmacology and Chemistry/Biochemistry at the University of California, San Diego, in collaboration with Steven M. Sine at the Mayo Foundation in Rochester, Minnesota. Visualized by Igor Tsigelny at SDSC” (San Diego Supercomputer Center, n.d.) There are two types of receptors, the neuronal or ganglionic receptors and the neuromuscular receptors. The neuronal receptors are located in the central nervous system that controls the brain and spinal cord of vertebrates and also on all autonomic ganglia, a collection of neurons in the autonomic nervous system. The neuromuscular type is responsible for muscle contraction which is done when receptors in the neuromuscular junctions of somatic muscles are activated (“Nicotinic acetylcholine receptors”, n.d.). The nicotinic receptors are composed of subunits that can be classified as multigene which means that different mixture of these subunits can produce a variety of receptors that have highly diverse kinetic, electrophysiological and pharmacological properties with multifaceted reactions to varying amounts of nicotine. This diversity makes the participation in the two major types of neurotransmission possible, the classical synaptic and the paracrine transmission. The action of the classical synaptic transmission is the scattering of signals to adjacent receptors referred to as the wiring transmission. The paracine or volume transmission is done by signal transfer per synaptic button or varicosities. It does not involve receptor to receptor transmission but rather through extra-cellular medium until ultimately reaching the receptors. In neuronal types, receptors are located either in post-synapse which functions for classical neurotransmission or in pre-synapse for neurotransmitter discharge (“Nicotinic acetylcholine receptors”, 2006). There are changeable conformational states of nicotinic AChRs. One is the open state that permits the entry of positive ions such as sodium, potassium and in some cases calcium into the cell in about 25 pS conductance which is possible by the binding of nicotine in the receptors (Siegel et al., 1999). The conductance is affected by the composition of the subunit. One example is the neuronal nAChRs permeable to Ca2+ wherein the conductance influences the dispersal of neurotransmitters (Itier and Bertrand, 2001). The agonist keeps the pore open for approximately 1 millisecond before it diffuses away (Siegel et al., 1999). There are also cases when the AChRs can access the opening with or without an agonist which then shuts down upon the ACh binding (Colquhoun and Sivilotti, 2004; “Nicotinic acetylcholine receptors”, 2006). Nicotine stimulates the neurons through two mechanisms. One mechanism is through the movement of cations that affects the ionic charge of the plasma membrane. This results in the stimulation of the neurons and ion channels that are activated through the chances in voltage or charges. Another is the possible effect of the calcium on the intracellular process ultimately regulates some genetic actions and causes the dispersal of neurotransmitters (“Nicotinic acetylcholine receptors”, 2006). Much interest is given to the pharmacological aspect related to the function of the receptors specifically in the plasma membrane of the cells. The main focus is its connection on conditions such schizophrenia, depression as an effect of aminergic receptor dysfunction and stomach acid production in relation to H2 receptor functions. Though extensive studies are being conducted, there are no results yet as to the specific relationship of nicotinic acetylcholine receptors (nAChR) to any ailment (Salamone and Zhou, n.d.). Certain examples of the possible relationship are presented. Results show that nicotinic receptors moderates nicotine addiction. Toxins in venoms target these receptors that lead their effects. Anaesthesia functions by using neuromuscular blocking agents that bind to the receptors. Another case is that for myasthenia gravis, wherein muscle weakness resulted the attack of antibodies on the receptors (“Acetylcholine receptor”, 2006). Proper functioning of the nicotinic receptors is essential in brain functions. Change in the form and function can be attributed to conditions such as Alzheimer's disease and schizophrenia. Data show that although the nAChR is not the main factor that affects conditions such as that of ADNFLE and the SCCMS, it plays a significant role that can be tapped when therapeutic need arise (Salamone and Zhou, n.d.). Nicotinic acetylcholine receptor and Alzheimer's Disease Evidences presented by different groups showed that the number of functional nicotinic binding sites in the brain decreased in patients with Alzheimer's disease (AD). In the study of Whitehouse et al., 19 AD patients were compared to 13 others with no indications of the disease. Through histopathology investigation, in the AD patients the levels of 3H ACh and 3H (-) nicotine binding was reduced which in most cases reaches to 50% in the frontal, temporal and occipital cortices, while the muscarinic receptors are unaffected (Collerton, 1986). Another observation is the decrease in the amount of choline acetyltransferase needed in the manufacture of Ach (Collerton, 1986; Bird et al, 1983). Images of the brain neurotransmitter binding, made possible by the positron emission tomography (PET), showed that there is comparatively less 11C (-) nicotine binding in AD patients in the different parts of the brain and the difference dictates the acuteness of the condition (Nordberg, 1993; Nordberg, 1995). In the study of the effects of drugs in the nicotinic receptors, results showed that cholinergic drugs, such as nicotine, enhance the intellectual functions as opposed to the effects brought about by anticotinic drugs. Although this is the case, further study is required since nicotine’s potency relies on the dosage and dose schedules. These results led to the generalisation of the cholinergic theory that attention and memory disintegration in patients with AD is due to the deterioration of the cholinergic system responsible for the maintenance of such functions (Salamone and Zhou, n.d.). In finding cure for the disease, drugs that have the same effect as nicotine are formed. Abbott Laboratories has produced ABT-418 that brought about improvement in the functions of aged monkeys with approximately 11% above baseline accuracy. Reversible acetyl cholinesterase inhibitors are most commonly used for AD patients. One of the drugs under this group is Tacrine that improve recall, word comprehension, and other intellectual functions in 238 patients studied and doses higher that 80 mg postpone the need for nursing home care (Salamone and Zhou, n.d.). Another significant characteristic of nicotine in the fight against AD is the prevention of transformation of precursor -peptides to form oligomeric -sheets, an indication of the disease (Birtwistle, 1996). Reduction in the toxicity of -amyloid can also be attributed to the activity of the receptor (Jones, 1992). The results of the different studies affirm the hypothesis that the process is non-pathway dependent, thus, cholinergic treatment is possible although further determination of the molecular progression is required. Upon the acquisition of such details, agonist can function on specified and directed manner to counteract neurodegenerative conditions (Salamone and Zhou, n.d.). Nicotinic acetylcholine receptor and Schizophrenia Based on a recent study, the effect of 7 nAChR in the onset of schizophrenia was presented (Lee et al, 1978; Roth et al, 1998). It was also observed that schizophrenics have higher possibility of being a smoker 2.6 times more than non-schizophrenics, thus, the relationship between nicotine and the disease was extrapolated (Iskedjian et al, 1998). Another focus of the study is the medication given to the patients. According to the specialists, there is a possibility that it targets the nicotinic receptors due to the probable relationship between nicotine and schizophrenia (Davies et al, 1998). Genetic linkage studies dawn the first indication of the effect of 7 neuronal nicotinic receptor in schizophrenia with the use of schizotactic markers. Some perceivable characteristic found in the lineage of patients with this condition are eye movement dysfunction and the p50 evoked potential gating deficit (Lee et al, 1978; Egan and Weinberger, 1997). Schizophrenia can be determined through marker, although in some cases these markers may be absent. The stress-diathesis model deals with the detection of the disease through monitoring of these factors. This was conducted through the study of the abnormality of the portion in the chromosomes that has the genes, which expresses schizophrenia upon stimulation. One indication of schizophrenia is being hypersensitive to noise. Schizophrenics usually keep non-systemic sounds out, an example of which is the humming of air conditioner. Observing such indication is important in understanding patients. This is because their reaction to situations such as these is often out of the ordinary and in most cases violent for they may perceive that the situation is dangerous. In the study conducted by Wahlberg et al, he stated that "the inability to process information and to sustain focal attention selectively may...share a vulnerability substrate with disordered thought", thus, providing the probable reason for such behaviours. This also serves as an indication that particular aspect of neurophysiologic deficit in schizophrenics can be obtained through the evaluation and determination of p50 (Wahlberg et al, 1997; Salamone and Zhou, n.d.). A significant observation is that p50 deficit was regulated in providing nicotine to the patients and the non-gating relatives. The p50 deficit can be located in the locus 15q13-14. This location is adjacent to the 7 neuronal nAChR location. Through the use of autoradiography techniques, proofs were derived regarding the connection between schizophrenia and neuronal nicotinic receptor. Evidence was discovered demonstrating a reduction in the amount of 7 subunit, a component of nicotinic receptor. It is in the hippocampi of almost all the 8 schizophrenics and 8 age matched controls which was monitored by using the postmortem 125I-Btx binding technique. The third evidence is the significant reduction in 3H-cytosine binding observed in schizophrenic patients. Through these three classifications of evidence on the pathophysiology of schizophrenia presented, it was proposed that nicotinic receptors stimulate the action of GABAergic inhibitory pathways. Such pathway prevents generation of feedback to repetitive stimuli. Freedman and his colleagues discussed the hypothesis on the role of 7 nAChR in the pathogenesis of schizophrenia. They also focused on the physiologic, morphologic and genetic aspects and give significant data gathered regarding the disease. The results of these research and that for AD is covered by the cholinergic hypothesis. These falls under the study on nicotinic receptor and pharmacotherapeutic research (Salamone and Zhou, n.d.). Conclusion The study of nicotinic acetylcholine receptor is important due to its effects on certain diseases. This study is aimed to present the role of nAChR at the molecular level that ultimately affects the functioning of the body at the systemic level. Some of the abnormalities of the nicotinic receptor are missense mutations, changes in gross channel density, and other genetic aberrations. In relation to this, the probability of having alterations in the primary amino acid sequence of the receptor is very minimal and can only be passed through Mendelian ways which is usually accompanied by alterations in the biophysical characteristic of the channel. On the other hand, changes in the concentration of these channels in significant parts of the brain lead to neurodegenerative conditions such as schizophrenia and Alzheimer's disease (AD). Through the gathered data, research on the possible treatments that targets the function of the nicotinic receptors and the agonists are being undertaken. In-depth study of the cholinergic dysfunction and its mode of action can lead to the discovery of more advanced treatments (Salamone and Zhou, n.d.). Reference List “Acetylcholine receptor.” (2006). Wikipedia. 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