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

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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Page 1: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

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.
Page 2: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

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.
Page 3: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

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.
Page 4: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

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.
Page 5: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

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.
Page 6: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

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.
Page 7: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

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.
Page 8: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

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 receptor from being activated. The important thing about a competitive antagonist is that it competes with acetylcholine and as the concentration of acetylcholine increases it can overcome the competitive antagonist and activate the receptor. Examples of competative antagonists include most of our neuromuscular blockers such as rocuronium, vecuronium, pancuronium, and cisatricurium. A non-competitive antagonist does not bind directly to the ligand binding site on the receptor. These ligands can either sit in the channel and block it from allowing any ions to pass through, or they bind to the receptor at an allosteric site. Both of these actions prohibit the activation of the nAChR and the flow of ions through the channel. The key difference with a non-competative antagonist is that the the concentration of acetylcholine has no effects of the action of this antagonist. Anesthetics that are noncompetative antagonists include our local anesthetics and inhalations agents.
Page 9: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

http://www.biochem.arizona.edu/classes/bioc462/462a/NOTES/LIPIDS/transport.html

Presenter
Presentation Notes
As previously stated the gate is located in the TMD and is created by the M2 helices of the 5 subunits. The M2 helix of each subunits tilts inward toward the center of the channel where they come together to form a barrier to ion permeation. The opening of the gate occurs through a twisting mechasnism. Once the receptor is activated through the binding of an agonist the extracellular domain and the transmembrane domain twist in the opposite directions. This twisting motion allows the M2 helices in the transmembrane domain to move toward the outside of the receptor resulting in an increase in the diameter of the channel making the opening large enough to allow ions to flow through.
Page 10: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

http://physiwiki.wetpaint.com/page/Autonomic+Nervous+System

Presenter
Presentation Notes
The one type of nAChR that we are the most concerned about and are fairly familiar with as anesthesia providers is the muscle-type nAChR. This receptor is located in the peripheral nervous system at the NMJ where the motor nerves innervate the muscles. As you can see in this figure of a NMJ, the nAChR are located within the subneural clefts. Muscle-type receptors are the type of receptors that as the name implies aid in muscle contraction. This receptor is activated by acetylcholine that is released from a motor neuron in response to an action potential on the nerve. The binding of acetylcholine causes a confirmational change opening the gate of the channel. The activated receptor allows sodium ions to flow through the ion channel into the muscle cell resutling in an increase in the membrane potential of the muscle and a possible action potential if threshold is reached ultimately causing muscle contraction.
Page 11: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

http://www.frca.co.uk/article.aspx?articleid=100618#

Presenter
Presentation Notes
In addition to the nAChRs location in the subneural cleft of the NMJ there are also presynaptic and extrajenctional nAChRs present at the NMJ. The presynaptic nAChRs play a role in a positive feedback loop. Activation of these receptors causes mobilization and synthesis of Acetylcholine in the nerve terminal though a second messenger system. This is responsible for the safety margin which is a mechanism to ensure that depolarization of the muscle cell and therefore a muscle contraction does occur. The extrajunctional nAChRs can be located anywhere on the muscle usually in small numbers but are mostly found concentrated by the motor nerve endplate. These receptors are different in that their subunit makeup is that of a fetal nAChR which are the alpha, beta, delta, and gamma subunits, even in the adult.
Page 12: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

Kalamida et al., 2007 http://www.cnsforum.com/imagebank/item/Rcpt_sys_ACH_dist/default.aspx

Presenter
Presentation Notes
The next type of nAChR is the neuronal-type with is present throughout the central and peripheral nervous system. We all are aware of the presence of the nAChR is the NMJ but I wanted to show this diagram to show how vast the receptor is in the CNS The nAChR plays an important role in the CNS’s functions of neuroprotection/neurodegeneration, learning, memory, reward, motor control, arousal, and analgesia. They can be located presynaptically, perisynaptically, and postsynaptically. The receptors that are located presynaptically and perisynaptically are responsible for regulating the release of neurotransmitters from the presynaptic neuron. The receptors that are on the postsynaptic neuron are responsible for the functions of neuronal excitability, gene expression, cell differentiation, and cell survival. On some neurons the activation of the nAChR can cause an action potential to fire through the excitation of the cell, while in other neurons the activation of the receptor is only facilitative by raising the resting membrane potential closer to threshold without causing an action potential to fire. In the PNS. They can be found in the autonomic nervous system and play a role in parasympathetic and sympathetic function. They are specifically located at the junction of the preganglionic and postganglionic neuron in both the ANS pathways. When acetylcholine binds the these receptors in both the sympathetic and parasympathetic pathways it causes excitation of the postganglionic neurons.
Page 13: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

Selective to calcium Increases intracellular

calcium by: • Direct influx • VOCC • Release from intracellular

stores

http://www.bath.ac.uk/bio-sci/research/profiles/wonnacott-s.html

Presenter
Presentation Notes
One of the key differences between the muscle-type and neuronal-type receptors is the primary ion involved in cellular excitation. The muscle-type nAChR allows the movement of mainly Na ion while the Neuronal-type nAChR are very selective to calcium ions. Neuronal-type receptors mediate an increase in intracellular calcium needed for the cell to carry out its functions by 3 mechanisms. 1.)direct permeation of calcium through the nAChR. 2.)An influx of calcium results in membrane depolarization causing the activation of voltage-gated calcium channels as well as 3.) triggers further release of calcium from intracellular stores. This generates prolonged calcium signals. The direct influx of Ca through the receptor and indirect influx of Ca through the activated voltage gated channels regulate the release of neurotransmitters. Another function of the influx of Ca into the cell is the initiation of the mechanisms that lead to memory formation. Lastly, the activation of the receptor results in second messenger Ca signaling which influences cell signaling, gene expression, and metabolism.
Page 14: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

Location Endocrine Endothelial Epithelial Immune

Composition Hetero/Homomeric All 17 subunit

subtypes

http://www.hindawi.com/journals/mi/2010/642462/fig1/

Presenter
Presentation Notes
Non-neuronal type receptors are found in numerous locations and aid in various functions. The receptor can be found in endocrine, endothelial, epithelial, and immune system cells to name a few of the specific locations of the non-neuronal nAChR. The composition of the non-neuronal nAChR differs according to the cells function in addition to internal and external environment conditions. The makeup of the non-neuronal nAChR have been found to be both hetero and homomeric and may contain any of the 17 subunit subtypes. In the epithelial cells the nAChR plays a role in the cell cycle and cell differentiation, facilitation of cell migration through chemotaxis, control of the cytoskeleton, participation in wound healing, and stimulation of the proliferation of airway epithelial cells. The receptors located in the immune cells cause release mediators such as prostaniods, leukotrienes, and chemokines, generation of antibodies, and inhibition of the release of proinflammatory mediators as part of the cholinergic anti-inflammatory pathway. The diagram demonstrates the anti-inflammatory function of the nAChR. The presence of inflammation stimulates the vagus nerve to release acetylcholine which inhibits proinflammatory mediators that are released from immune cells such as Interleukins, tumor necrosis factor, and the cytokine high mobility group box 1. Activation of the nAChR can be done physiologically with acetylcholine or pharmacologically with nAChR agonists.
Page 15: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

MEMORY MUSCLE CONTRACTION

Presenter
Presentation Notes
Now that we have discussed the anatomy and physiology of the nAChR in addition to its vast locations throughout the body and wide range of functions, you can see how this receptor is responsible for certain activities that we want to affect with the administration of our anesthetics. As anesthesia providers we manipulate this receptor to be able to achieve our anesthetic goals for our patients. We are able to achieve these goals through the administration of multiple anesthetic agents and adjunts that affect and manipulate the nAChR. 2 of the main goals that we strive to achieve through the administration of anesthesia are to suppress the formation of memories and to prevent movement of the patient.
Page 16: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

General anesthetics Non-competitive

antagonist

Inhibits calcium permeability of the cell

Presenter
Presentation Notes
General anesthesia affects the neuronal-type nAChR in the CNS. The effects that occur as result of general anesthetics affects on the neuronal-type receptor include amnesia, lack of attention, behavioral states, and delirium. General anesthetics act as noncompetative antagonists and produce an inhibitory affect on the neuronal-type receptors. The exact mechanism of action of the general anesthetics remains undertermined and may act in one of the two ways demonstrated by a noncompetative antagonist. These mechanisms include the binding of a ligand on an allosteric site of the receptor which provokes a nonconductional state or through the ligand entering the ion channel and blocking it to inhibit the flow of ions. As stated earlier neuronal-type nAChRs have an increased permeability to Ca ions which promotes the activation of the mechanisms needed to lead to memory formation. Without the ability for Ca to enter the cell, the cell is unable to initiate these processes and the formation of memories cannot take place.
Page 17: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

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

•Local anesthetics

•Non-depolarizing muscle relaxants

•Depolarizing muscle relaxants •Inhalational agents

Presenter
Presentation Notes
Anesthetics and adjunct agents that are administered to attenuate muscle contraction have their effects on the muscle-type nAChR at the NMJ. The actions of these anesthetics of the muscle-type receptor inhibits the influx of Na into the muscle cell and therefore an action potential that leads to muscle contraction cannot be initiated. One adjunct agent that has some affects on the nAChR at the NMJ includes local anesthetics. Local anesthetics primarily inhibit voltage-gated Na channels, but they also function as a noncompetative antagonist at the nAChR to depress the synaptic transmission from the motor neuron to the muscle cell. Researchers disagree on the exact mechanism of action of local anesthetics and may act through binding to allosteric sites on the receptor to inhibit channel opening, or they may act by entering the ion channel of the receptor to form a blockade which prevent the flow of Na ions into the muscle cell. Another agent that affects the nAChR at the NMJ is nondepolarizing muscle relaxants. These agents produce their effects on the receptor by acting as competitive antagonists. Therefore nondepolarizing muscle relaxants compete with acetylcholine to bind to the ligand binding site on the alpha subunits of the recetpor. Because these agents compete with acetylcholine their affects can be supressed by a local increase in the concentration of acetylcholine at the NMJ. Since 2 acetylcholine ligands are needed to bind to the alpha binding sites on the nAChR, only 1 ligand of the nondepolarizing muscle relaxant is needed to bind to the receptor to prevent it from becoming activated causing the ion channel to open. In addition to having affects on the postsynaptic nAChR on the muscle cells these agents also have affect presynaptic nAChR at the NMJ therefore altering the mobilization and synthesis of acetylcholine in the motor nerve terminal. When using a nerve stimulator to monitor the effects of these drugs on your patients you will see a fade with tetany and TOF. This is because the nondepolerizing muscle relaxants prevent enough acetylcholine from being made fast enough to support tetany and TOF. In other words it deminished the safety margin. Also, these agents produce a slow onset and slow recovery. Depolarizing muscle relaxants is another adjuct agent affecting the nAChR at the NMJ. These agents produce their effects by acting as an agonist for the receptor. Because these agents are agonists, 2 lignads on the depolarizing muscle relaxant is needed to bind to the binding sites on the alpha subunits to cause activation of the receptor. Once these agents cause the receptor to become activated Na ions rush through the channel and an action potential is fired resulting in muscle contractions, clinically this is seen as muscle fasiculations. A high amount of depolarizing muscle relaxant is present at the NMJ and equilibrated with the binding sites on the nAChR. This high concentration of molecules causes the receptor to transform into a desensitized state in which the ion gate closes and the receptor cannot be activated until the depolarizing muscle relaxant ligands are removed from the binding sites on the receptor. Again this agent also affects presynaptice nAChRs in addition to the postjunctional receptors on the muscle cells resulting in an increase in mobalization and synthesis of acetylcholine at the motor nerve ending. This is the reason that when you are monitor depolarizing muscle relaxants with a nerve stimulator there is a constant TOF with no fade present. This is also the reason that you need a higher dose of nondepolarizing muscle relaxants after the administration of depolarizing muscle relaxants. The depolarizing agent increases the amount of acetylcholine in the NMJ and a higher dose of nondepolarizing agent is needed to overcome the increased concentration of acetylcholine and be effective. Depolarizng muscle relaxants in contrast with nondepolarizng agents have a fast onset and fast recovery. It is also important to mention that due to physiological and pharmacolocal changes between the adult and fetal muscle-type nAChR, there is a increased sensitivity with depolarized relaxants and a decreased sensitivity with nondepolarizing relaxants to the fetal muscle-type receptor. Lastly, inhalational agents, although are more sensitive to neuronal-type nAChRs, exhibit some affects on the muscle-type nAChR at the NMJ. These anesthetic agents act as noncompetative antagonists and with their use, they may decrease the amount of muscle relaxants needed to prevent the activation of the nAChR and therefore muscle contraction.
Page 18: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

Rossman, 2011

Presenter
Presentation Notes
This is just a table showing an overview of the effects of anesthetic agents and adjuncts on the different types of nAChRs. Inhalations anesthetics also minimally affect the muscle type nAChRs which is not shown up there.
Page 19: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

Upregulated Receptors

Downregulated Receptors

Diseases Upper/Lower motor neuron lesions, burns,

immobilization, denervation injuries

Myasthenia Gravis, congenital myasthenic

syndromes

Depolarizing muscle relaxants

Nondepolarizing muscle relaxants

Presenter
Presentation Notes
There are numerous disease processes that can affects the nAChRs… I am not going to go in depth about each disease but I will say how certain disease process can influence the nAChR and how that can affect how we administer out anesthetics to these particular patients. Certain pathophysiological process can either cause upregulation or downregulation of the muscle-type nAChR. The disease/injuries that will cause the upregulation include upper and lower motor neuron lesions, patients with burns, patients who are immobalized for a period of time, and patients who have denervation injuries. The important thing about these disease processess is that when the muscle-type nAChR is upregulated it is the extra-junctional receptors that actually increase, so as I mentioned earlier in the presentation the extrajunctional receptors have the subunit makeup of the fetal musle-type nAChRs. So what does this mean for the administration of anesthesia? The most important thing to remember with these patients is that you should not give them any depolarizing muscle relaxants because it could be fatal. The reason for this is due to the fact that the extrajunctional fetal receptors are more sensative to the depolarizing muscle relaxants which can cause a large amount of K release from the cells and lead to cardiac arrest from hyperkalemia. In regards to nondepolarizing muscle relaxants, these patients will have an increased requirement due to the decreased sensativity of these agents to the extrajunctional nAChR receptors. Diseases that lead to a downregulation of the muscle-type nAChR are myasthenia gravis and congenital myasthenic syndromes. Due a decrease in the amount of receptors in the NMJ these patients will have an increased requirement for depolarizing agents and a decreased requirement for nondepolarizing agents. Both depolarizing and nondepolarizing muscle relaxants should be used with caution in patients with neuromuscular and musculoskeletal diseases. Certain disease process carry the risk of hyperkalemia and cardiac arrest while other may cause prolongation of muscle relaxation leading to muscle weakness and an increase time to recovery. I also quickly want to mention that pathophysiological functions of the neuronl-type nAChR are not well defined and that clinical data has suggested their involvement in pathogensis of certain disorders including Alzheimer’s disaese, Parkinson’s disease, schizophrenia, autism, hereditary epilepsies, and smoking addiction.
Page 20: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

Located widely throughout the body and is involved in numerous bodily functions. • Muscle, neuronal, and non-neuronal types

This is the target of many anesthetics that we will use. • Muscle contraction and memory

Understanding of this receptor will help us to appropriately reach the anesthetic goals for our patient.

Presenter
Presentation Notes
The nAChR has a complex composition and diverse locations and functions throughout the body. Because of its varied functions from aiding in muscle contraction to assisting in the formation of memories, the nAChR is one of the most important receptors that the nurse anesthetists focuses on during the administration of anesthesia. Many of the goals we strive to achieve through our anesthetics is done through the manipulation of this receptor. Having a full understanding of the nAChR and its functions allows us to fully be able to better achieve these goals and provide a more appropriate, complete, and safe anesthetic for our patients.
Page 21: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program
Presenter
Presentation Notes
Phase II Block – Develops with repeated doses of a depolarizing muscle relaxant or for long periods of continuous dosing and results in a slow recovery from muscle blockade. The mechanism of a phase II block remains controversial. One thought is that the continuous depolarization of the nAChR can upset the ionic balance of the cell and once the depolarizing agent is stopped and is released from the binding site, which occurs quickly, the muscle cell needs time to restore it’s normal intracellular ion concentrations before it can again be activated. Thus possibly leading to the cause in the prolonged recovery from a phase II block.
Page 22: The Nicotinic Acetylcholine Receptor...The Nicotinic Acetylcholine Receptor (nAChR) Amanda Rossman RN, BSN, SRNA York College of Pennsylvania/ Wellspan Health Nurse Anesthesia program

Arias, H. R., & Bhumireddy, P. (2005). Anesthetics as chemical tools to study the structure and function of the nicotinic acetycholine receptors. Current Protein and Peptide Science, 6, 451-472.

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Gotti, C., Riganti, L., Vailati, S., & Clementi, F. (2006). Brain neuronal nicotinic receptors as new targets for drug discovery. Current Pharmaceutical Design, 12, 407-428.

Kalamida, D., Poulas, K., Avramopoulou, V., Fostieri, E., Lagoumintzis, G., Lazaridis, K.,...Tzartos, S. J. (2007). Muscle and neuronal nicotinic acetylcholine receptors structure, function, and pathogenicity. FEBS Journal, 274, 3799-3845, doi: 10.1111/j.1742-4658.2007.05935.x

Lecchi, M., Hoda, J., Hogg, R., & Bertrand, D. (2010). Cys loop receptors. In J. Kew & C. Davies (Eds.), Ion channels: From structure to function (pp. 209-221). New York, New York: OXFORD University Press.

Lu, Z. and Yu, B. (2007) Role of presynaptic acetylchioline autoreceptors at motor nerve ending on tetanic and train-of-four fade seen during a nondeploarizing neuromuscular block. Anesthesiology, 106, 1243

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