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The Nicotinic Acetylcholine Receptor ... The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

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  • The Nicotinic Acetylcholine Receptor

    (nAChR)

    Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/Wellspan Health

    Nurse Anesthesia program

    Presenter Presentation Notes First, I would like to thank everyone for coming out this evening to listen to myself and the other students present.

    Tonight I am going to be discussing the nAChR and its importance in the administration of Anesthesia. I am sure everyone here can remember back to the day is anesthesia school when they learned about this receptor and how it is affected when we administer our anesthetic. Tonight I thought that it would be a good idea to go back to the basics and review both the anatomy and physiology of the nAChR. Due to the time limit and large amount of information that could be discussed about this topic, anatomy and physiology of the nAChR will remain my focus with only mentioning a few key points about pathophysiology.

  •  Overview  Receptor composition  Structure of the receptor  How the receptor is activated

    • What activates the receptor • How the ion channel opens

     Types and functions of the receptor  Why this receptor is important to the practice

    of anesthesia

    Presenter Presentation Notes What to expect throughout the presentation includes: An overview of the nAChR Composition including the different subunits and subunit subtypes Structure including the make-up and different parts of the receptor The activation of the receptor The different types of nAChRs and the function of each Lastly, the most important part – why this receptor is important to the administration of anesthesia.

  •  Locations: • Peripheral Nervous System • Central Nervous System

     Types: • Muscle-type • Neuronal-type • Non-neuronal type

     Functions • Dependent upon location and composition

    http://www.jbc.org/content/283/32.cover-expansion

    Presenter Presentation Notes The nAChR is the most researched and best understood receptor of the ligand gated channel family. Most of the knowledge of this receptor has come from research done on torpedo fish nAChR and mollusks acetylcholine binding protein because they are most similar to the human nAChR.

    The nAChR is a integral protein that is a ligand gated ion channel allowing communication between the intracellular and extracellular compartments through the movement of ions.

    The nAChR can be found at many locations within the body including throughout the CNS and the PNS.

    The three different types of the nAChR are the muscle-type, neuronal-type, and the non-neuronal-type which I will explain in greater detail later in the presentation.

    The function of the nAChR depends on numerous factors including its location in the CNS or PNS and the subunits and their subtypes that constitute a particular receptor. The generalized function of the nAChR is to transform chemical signals into electrical signals by taking extracellular acetylcholine and using it to generate an electrical signal resulting from the opening of ion channels. This is done by opening a ligand gated channel and allowing an influx of cations into the cell.

  • SUBUNITS

     α  β  δ  γ  ε

    SUBTYPES

     α 1-10  β 1-4

    Rossman, 2011

    Presenter Presentation Notes The nAChR is composed of subunits consisting of precise combinations of subtypes that mediate its assorted physiological functions.

    The nAChR is made up of 5 subunits which are alpha, beta, gamma, delta, epsilon. But the nAChR always contain at least 2 alpha subunits.

    The subunits are further categorized into 17 subunit subtypes which contribute to the receptors complexity. These subunit subtypes include: alpha 1-10, beta 1-4, gamma, delta, and epsilon.

    Each type of nAChR only contain specific subunit subtypes. Alpha 1, beta 1, gamma, delta, and epsilon are expressed in the muscle-type nAChR and alpha 2-10 and beta 2-4 subunit subtypes are expressed in the neuronal-type receptors. The non-neuronal nAChR have been found to contain all of the different subunit subtypes.

  • http://www.jyi.org/research/re.php?id=88

    Presenter Presentation Notes Muscle-type receptors are heteromeric which mean that it us made up of multiple subunits. The subunit composition in the muscle-type nAChR is 2 alpha1, beta1, delta, and a gamma or epsilon subunit. The muscle-type receptors that contain a gamma subunit are the composition of fetal muscle nAChRs, which is the receptor shown in this picture. In the adult muscle-type nAChR the gamma subunit is replaced with an epsilon.

    Neuronal-type receptors can be either heteromeric or homomeric which mean that the subunits and subunit subtypes are the same. The most common heteromeric make-up is 2 alpha4 and 3 beta2, one of the more common homomeric make-up is 5 alpha7.

  • 1. Extracellular domain - Binding sites

    2. Transmembrane domain - Channel gate

    3. Intracellular domain - Regulates expression

    Zouridakis et al., 2009

    Presenter Presentation Notes Composed of 3 domains The extracellular domain composed of 10 beta strands, known as a beta sheet, that are connected by a cys-loop. The binding sites for acetylcholine as well as our anesthetics are located on the ECD. The alpha subunit is the principal component of the binding site formed by loops A, B, and C which you can see in the figure as this is an alpha subunit, and the non-alpha adjacent subunit (either the beta, delta, gamma, or epsilon) is the complementary component of the binding site formed by loops D, E, and F. The heterometic receptors contain 2 binding sites as they contain 2 alpha subunits. The homomeric receptors are suggested to contain 5 binding sites as they contain 5 alpha subunits with each alpha subunit containing both the principal and complementary binding sites. The transmembrane domain is the area of the receptor that spans the cell membrane and forms the ion pore. It is made up of 4 helices M1, M2, M3, M4. A covalent bond exists between the M1 helixes and the B10 chain of the ECD to join these 2 domains together. The M1, M3, and M4 helix form an outer ring while the M2 helix from each of the 5 subunits is on the inside and make up the walls of the channel pore through which the ions flow. The ion gate is also located in the TMD and is created by the M2 helix. The intracellular domain contains another helix called the MA helix. The MA helices from all of the 5 subunits form the intracellular vestibule of the nAChR. The ICD contains the M3-M4 loop which is believed to be important in the export of the nAChR form the endoplasmic reticulum and the regulation of trafficking and expression by promoting clustering of the receptor. This domain is also instrumental in the assembly and and anchoring of the receptor to the cell membrane.

    All 3 domains of the receptor are lined with negatively charged amino acid residues that allow it to be selectively permeable to cations including sodium, potassium, and calcium. This negative charge then causes the receptor to repel anions. The diameter of the nAChR is 20-25 amstrums, with the narrows portion measuring 7 ampstrums. The measurement of the receptor diameter when it is activated and the gate open is just wide enough to allow the passage of the cations to flow across the cell membrane therefore also resulting in the receptor’s selective permeability.

  • http://www.medicine.mcgill.ca/mjm/issues/v05n02/v05p090/v05p090fgr2.htm

    1. 2.

    3.

    Presenter Presentation Notes The nAChR has 3 conformational stages.

    1.)When the binding sites of the ECD is free of ligands, the receptor is in the Resting state. During this state the gate is closed and it is able to activated through the binding of acetylcholine or an exogenous ligand.

    2.)Upon binding of a ligand to the binding sites the receptor undergoes a confirmational change and is in the activated state. This confirmational change opens the gate to the ion channel and allows the cations to flow through. The activation state can only commence once all of the binding sites contain a ligand.

    3.)When a ligand remains bound to the receptor binding site the receptor transitions into the a desensatized state where the gate closes and the flow of ions ceases. During this state the receptor is refractory to the ligand and cannot be activated. Once the ligand is removed from the binding site the receptor transforms back into the resting state where is can be activated once again.

  • Rossman, 2011

    Presenter Presentation Notes Ligand binding proteins can have different effects on the action of the receptor.

    A ligand that elicit these effects through binding to the nAChR are agonists or antagnosists, with antagonists being broken down into competitive or non-competitive antagonists. These binding proteins are specific to the subunit makeup of the nAChR as demonstrated by ligands that have certain effects on one nAChR may have have a different effect on another nAChR with a different makeup of subunits.

    An agonist is a ligand that binds to the ligand binding site on the Extracellular domain. The binding of an agonist results in the activation of the receptor causing the gate to open. To two most common agonists include succinylcholine and acetylcholine.

    An Antagonist is a ligand that does not cause any specific action to take place. A competitive antagonist also binds to the ligand binding site on the extracellular domain and prohibits the binding of an agonist, therefore inhibiting the

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