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Possible Essay Questions: The following are possible long essay questions that will be asked on exam II – total points from the long essay portion will be 15. To be fully prepared you should be able to write on a number of these topics as well as the clinical applications topics from your study guides which will account for 5-10 points. The exam will also contain general questions that pertain to the Key Medical Terms. All the best to you in your preparation and please do not hesitate to contact me if you have any questions about the material. Possible 15 Point Essay Questions

1. Describe a resting membrane potential (RMP) and how the RMP can change. Describe the

characteristics of a graded potential and an action potential and include a detailed labeled drawing of an action potential. Describe the steps in the formation of an action potential in a motor neuron starting with a neural impulse coming from the brain (a drawing is helpful but optional). Explain the components/functions of the refractory periods and include a detailed labeled drawing.

2. Describe the components of a sarcomere and sliding filament model of muscle contraction. Explain how skeletal muscles are innervated and the details of a motor unit. Draw and label a diagram of the neuromuscular junction and describe the functions of the structures that make up the neuromuscular junction. Explain the three steps involved in the contraction and relaxation of a skeletal muscle fiber.

3. Describe the function and structure of the thyroid gland and how it produces thyroid hormones. Be sure to include the details of parafollicular cells. Explain how thyroid hormone production/secretion is regulated. Describe how hypothyroidism is classified, the general symptoms of hypothyroidism and descriptions of 4 common hypothyroid disorders discussed in class. Describe the general symptoms of hyperthyroidism and the one common hyperthyroid disorder discussed in class.

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1. Describe a resting membrane potential (RMP) and how the RMP can change. Describe the characteristics of a graded potential and an action potential and include a detailed labeled drawing of an action potential. Describe the steps in the formation of an action potential in a motor neuron starting with a neural impulse coming from the brain (a drawing is helpful but optional). Explain the components/functions of the refractory periods and include a detailed labeled drawing.

Resting Membrane Potential

• A resting membrane potential (RMP) is a separation of opposite charges across a cell’s plasma membrane.

• The outside surface of the cell membrane has an overall positive charge as compared to the inside surface of the cell membrane which has an overall negative charge.

– Note: The resting membrane potential exists only across the membrane – the bulk of the solutions inside and outside the cell are electrically neutral

Changes in RMP are due to diffusion of ions down their electrochemical gradients, which underlie all electrical events in neurons and muscle cells.

• Electrochemical gradient is the combination of electrical and chemical concentration gradients

– Electrical gradients: Ions move toward an area of opposite electrical charge. – Chemical concentration gradients: Ions diffuse from an area of higher concentration

to an area of lower concentration. – Example: The electrochemical gradient of Na+ is due to Na+ attraction to the negative

change on the inside of the cell’s membrane and its concentration gradient – there is a higher concentration of Na+ outside the cell causing it to diffuse into the cell.

Characteristics of a Graded potential and an Action Potential

• Graded potentials (GP): Are short lived, local changes in the membrane potential. The charge/current spreads by diffusion of ions through the cytoplasm from the origination site.

• As the current spreads along a stretch of membrane it decreases in magnitude with distance – which is why it is called “graded” because its magnitude (amplitude) varies with stimulus strength– it depends on 1) how many ion channels were opened and 2) how many ions entered the cell.

• If the initial amplitude of the GP is sufficient, it will spread to the axon hillock where it can stimulate voltage-gated channels.

• An Action Potential (AP) or impulse is a brief electrochemical event in which the polarity of

the membrane potential is rapidly depolarized and then repolarized (reestablished). • AP are the principal way neurons and muscle cells send signals over long distances. • Unlike graded potentials, action potentials do not decrease in magnitude with

distance. • Action potentials are restricted to areas of excitable membrane, which contain

voltage-gated channels.

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Labeled drawing of an Action Potential

Steps in the formation of an Action Potential in a motor neuron 1. An action potential (neural impulse) travels down an upper motor neuron coming from the

brain and synapses with a lower motor neuron cell body/dendrites within the spinal cord. At the synaptic end bulbs the action potential stimulates voltage gated calcium channels to open and calcium flows into the synaptic end bulb. The inflow of calcium stimulates the release of acetylcholine (ACh) from ACh containing vesicles.

2. Acetylcholine (ACh) diffuses across the synaptic cleft and binds to the ACh receptors. These receptors are ligand-gated Na+ channels. ACh is the ligand that causes them to open.

a. Na+ rushes into the cell due to its electrochemical gradient, making the local cell interior more positive. This is known as a graded depolarization.

b. If the initial depolarization of the GP is sufficient, it will spread to the axon hillock where voltage-gated channels are located.

c. If the GP produces a depolarization that is at or above threshold, an action potential will be initiated at the axon hillock. If the depolarization is below threshold, then no AP will form and nothing will happen.

d. Threshold is the minimum stimulus that initiates an action potential. Threshold level for a motor neuron is -60 mV.

3. Action potential formation at axon hillock – Voltage gated sodium channel activation. a. If threshold (-60 mV) is reached, voltage-gated Na+ channels open. b. Na+ ions, driven by their electrochemical gradient, move into the cell and cause a

rapid depolarization – the transmembrane potential on the inner membrane surface goes from threshold to +20 mV in less than 1 millisecond.

i. Note the electrochemical gradient of Na+ is due to Na+ attraction to the negative change on the inside of the cell and its concentration gradient.

4. Sodium channel inactivation and potassium channel activation. a. Voltage gated Na+ channel rapidly close as the transmembrane potential reaches

+20 mV b. At +20 mV, voltage-gated K+ channels open and K+ moves out of the cell resulting

in repolarization - shifting the transmembrane potential back towards it resting membrane potential.

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5. Return to normal permeability

a. Voltage-gated Na+ channels remain inactivated until the membrane has repolarized to near the resting membrane potential (-70 mV), after which are closed but capable of opening if there is a strong enough stimulus to bring it back to threshold (-60 mV).

b. Voltage-gated K+ channels begin closing at -70 mV. Because they close slowly, excess K+ continues to move out of the cell, producing a brief hyperpolarization.

c. When all of the voltage-gated K+ channels close the membrane regains its normal properties as the Na+ K+ pumps reestablish the ion gradients.

6. The action potential travels all the way down to the axon to the synaptic end bulb where it stimulates voltage gated calcium channels to open and calcium flows into the synaptic end bulb. The inflow of calcium stimulates the release of acetylcholine (ACh) which diffuses across the synaptic cleft to stimulate the skeletal muscle.

Refractory Periods • Refractory period: Time that a muscle fiber or neuron will not respond normally to additional

depolarizing stimuli. – Starts at the beginning of an

action potential and ends when the RMP has stabilized

– Subdivided into absolute and relative refractory periods

• Absolute refractory Period: Time that the membrane will not respond to further stimulation because all the voltage-gated Na+ channels are either open or they are closed and incapable of opening (inactivated).

– Starts at threshold and ends when the membrane potential starts hyperpolarization (at -70 mV).

• Relative Refractory Period: Time that another action potential can begin if the membrane is depolarized to threshold, but that requires a larger than normal depolarizing stimulus because the membrane is hyperpolarized.

– The depolarizing current must deliver enough Na+ ions to counteract the loss of positively charged K+ ions during hyperpolarization.

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2. Describe the components of a sarcomere and sliding filament model of muscle contraction. Explain how skeletal muscles are innervated and the details of a motor unit. Draw and label a diagram of the neuromuscular junction and describe the functions of the structures that make up the neuromuscular junction. Explain the three steps involved in the contraction and relaxation of a skeletal muscle fiber.

Sarcomeres

• Sarcomere: The contractile unit in a striated muscle cell extending from one Z disc to the next Z disk.

– Each myofibril is made up 1000’s of repeating units known as sarcomeres

• The portion of the sarcomere which contains the thick filament is known as the A band.

– The “A” band contains a zone of overlap (between thick & thin filaments) and an “H” zone which contains only thick filaments

• The portion of the sarcomere which does not contain any thick filaments is known as the “I” band.

– The “I” band contains only thin filaments and The Z disk.

– Note: One “I” band is actually part of two sarcomeres at once.

• In the middle of the H zone is a structure called the M line which functions to hold the thick filaments to one another.

The Sliding Filament Model of Muscle Contraction

• Model describes the movement of thick (myosin) and thin (actin) filaments during contraction – During a contraction, thick and thin filaments do not shorten but increase their overlap – Thin filaments slide past thick filaments, extending more deeply into the A band, which

remains at constant length – I bands and H bands decrease in length as Z disks are drawn closer together. – Sarcomere represents area between successive Z disks, therefore the sarcomere gets

smaller during a contraction • When all the sarcomeres in a fiber do this the entire fiber gets shorter which pulls on the

attached tendon and then pulls on the bone. Voila, we have movement. Muscle Innervation and Motor Unit

• In general each muscle is innervated by one nerve. – A Nerve is a bundle of axons and/or dendrites carrying signals to or from the spinal

cord to the muscle or other structure. • A Motor unit consists of a motor neuron and all the skeletal muscle fibers it innervates.

– Muscles that control small precise movements have many motor units with few muscle fibers.

• Ex: Muscles of fingers and eyes – Muscles that cause large, powerful movements have few motor units with many muscle

fibers per motor unit. • Ex: Gastrocnemius and quadriceps muscles

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Labeled Diagram of Neuromuscular Junction Structures of the Neuromuscular Junction

• The Neuromuscular Junction is a synapse between a motor neuron and a myofiber.

• Within the skeletal muscle, the axon of each neuron will branch into multiple small extensions called the telodendria which end at the axon terminals.

• Each axon terminal has bulbous swellings known as synaptic end bulbs (terminal boutons), that are filled with vesicles containing the neurotransmitter acetylcholine.

• The synaptic cleft is the minute space between the axon terminal and the sarcolemma.

• The Motor end plate is the region (depression) of the sarcolemma that is adjacent to the synaptic end bulbs and contains acetylcholine receptors.

• The axon terminal is filled with vesicles that contain the neurotransmitter, acetylcholine. • The motor end plate has a number of junctional folds that increase the surface area. The

folds contain a number of acetylcholine receptors (nicotinic receptors) that are ligand gated sodium channels.

• Acetylcholinesterase is an enzyme located in the junctional folds that degrades acetylcholine, thus ending the depolarizing signal to the muscle cell.

There are 3 Steps to the Contraction and Relaxation of Skeletal Myofibers 1) Excitation of Neuron Terminal

• An action potential arrives at the axon terminal. • Depolarization of the axon terminal causes voltage gated calcium channels to open and

extracelluar calcium ions enter the axon by their electrochemical gradient. – The rise in Ca2+ triggers the synaptic vesicles within the synaptic endbulb to release

acetylcholine into the synaptic cleft by exocytosis. • Acetylcholine (ACh) diffuses across the synaptic cleft and binds to the ACh receptors.

These receptors are ligand-gated Na+ channels. ACh causes them to open. • Na+ moving down its electrochemical gradient, will rush into the cell depolarizing it

towards threshold • This is known as a graded depolarization.

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2) Excitation of the Myofiber • If threshold is reached within the myofiber, the action potential travels along the

sarcolemma and into the Transverse (T) tubules which carry the wave of depolarization deep into the muscle cell.

• At the triad, which consists of a central T tubule flanked on each side by terminal cisternae, the action potentials of the T tubules cause the voltage-gated dihydropyridine (DHP) receptors to change shape (conformational change). The activated DHP receptors are attached to calcium release channels (also called ryanodine receptors) of the terminal cisterns of the sarcoplasmic reticulum.

– This shape change causes the opening of calcium release channels allowing calcium to flow into the sarcoplasm.

• The Ca2+ binds specifically with troponin C of troponin causing a conformational change in the troponin-tropomyosin complex, which exposes attachment sites for the myosin head.

• The myosin head (cross-bridges),

attaches to actin. Note: The myosin head was previously activated by the attachment of ATP and its hydrolysis to ADP and P.

– ATP hydrolysis provides the energy for the “cocking” of the myosin head.

• Once attached to actin, the myosin head undergoes a power stroke and pulls the thin filaments over the thick filament.

– This results in the thin filament sliding along the thick filament.

– The ADP and P molecules are released.

• Myosin remains bound to actin until it binds to another ATP. Attachment of fresh ATP provides the energy to “cock” the myosin head back and detach it from the actin molecule. The cycle can repeat as long a calcium remains attached to troponin and ATP is available

Typically half the myosin molecules at any time are bound to the actin while the other half are preparing to bind again.

A common analogy is climbing a rope hand over hand. 3) Relaxation of the Myofiber

• Cessation of action potentials stops down the lower motor neuron stops the release of ACh and thus the formation of action potentials moving down the sarcolemma.

– The sarcoplasmic reticulum actively retrieves (sequesters) the calcium ions by pumping the calcium ions into the sarcoplasmic reticulum

– Without calcium, the troponin tropomyosin complex moves over the myosin binding site on the actin filament preventing attachment of the myosin heads (crossbridges) and the filaments side past each other elongating the sarcomere as the muscle relaxes.

• Note that ACh does not remain bound to the ACh Receptors at the neuromuscular junction for very long.

– It quickly releases and is broken down (hydrolyzed) by the enzyme acetylcholinesterase which exists as part of the sarcolemma and free within the synaptic cleft.

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3. Describe the function and structure of the thyroid gland and how it produces thyroid

hormones. Be sure to include the details of parafollicular cells. Explain how thyroid hormone production/secretion is regulated. Describe how hypothyroidism is classified, the general symptoms of hypothyroidism and descriptions of 4 common hypothyroid disorders discussed in class. Describe the general symptoms of hyperthyroidism and the one common hyperthyroid disorder discussed in class.

Thyroid Gland • The thyroid gland functions to regulate metabolism (basal metabolic rate) and the growth and

development of the body. • The thyroid gland, located just inferior to the larynx, is a butterfly-shaped gland that consists

of two lateral lobes connected by a narrow isthmus. – Contains parafollicular cells and numerous thyroid follicles, which are small spheres

lined with follicular cells that synthesize thyroid hormones that are stored in the follicles.

– Within the colloid of the follicles, an enzyme called thyroperoxidase attaches iodine to the amino acid tyrosine within the thyroglobulin protein molecule.

• Note: Iodine is essential for production of thyroid hormones

– Attachment of one iodide to tyrosine yields monoiodotyrosine (MIT); attachment of two iodides to tyrosine yields di-iodotyrosine (DIT)

– Coupling one MIT to one DIT yields T3 – Coupling two DIT yields T4 – Thyroid hormones include:

• Thyroxine or tetraiodothyronine (T4): Consists of 4 iodine molecules • Is converted to T3 within the target cells

• Triiodothronine (T3): Consists 3 iodine molecules and is the more active form. – Upon stimulation by thyroid stimulating hormone (TSH), the follicular cells take up a

portion of the colloid, remove thyroglobin from T3 and T4 and secrete the free hormones into the blood.

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• Parafollicular Cells (C cells)

– Located between the follicles. – Are also called “C” because they appear "clear"

(as in lighter staining). – Parafollicular cells synthesize and release

calcitonin in response to high blood calcium, which lowers blood calcium levels by:

• Stimulate osteoblast activity - calcium will be taken from the blood and deposited as bone matrix

• Stimulating calcium ion excretion at the kidneys

Regulation of Thyroid Hormone Production/Secretion

• Thyrotropin-releasing hormone (TRH) from the hypothalamus activates thyroid stimulating hormone (TSH) secretion by the anterior pituitary.

• Thyroid hormone (T3 and T4) secretion is regulated by TSH through negative feedback processes.

– Low levels of thyroid hormones induces the hypothalamus to release thyrotropin releasing hormone (TRH) which signals the anterior pituitary to release TSH

– TSH stimulates the thyroid gland to produce and secrete thyroid hormones.

– High levels of thyroid hormones inhibit the hypothalamus from releasing TRH and the anterior pituitary from releasing TSH resulting decreased thyroid hormone production.

Hypothyroidism Classification

• Hypothyroidism is classified into 3 different types based upon the organ that is malfunctioning and include: Primary, Secondary, and Tertiary

• Primary Hypothyroidism (most common) – Thyroid gland malfunction results in

decreased production of thyroid hormones. – Common causes: Hashimoto’s disease (an

autoimmune disorder), radioactive iodine therapy for hyperthyroidism, external radiation to treat tumors of the head and neck, and iodine deficiency.

• Secondary Hypothyroidism – Pituitary gland malfunction. The pituitary gland does

not create enough thyroid stimulating hormone (TSH) to induce the thyroid gland to create a sufficient quantity of thyroid hormones.

– Common causes: Pituitary is damaged by a tumor, radiation, or surgery.

Tertiary Disease

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• Tertiary Hypothyroidism

– Hypothalamus malfunction . Results in decreased production and/or reduced delivery of thyrotropin-releasing hormone (TRH) from the hypothalamus to the pituitary gland.

– Not very common. This condition can develop years after cranial irradiation.

Hypothyroid Disorders • Hyposecretion of thyroid hormones can result in:

– Low basal metabolic rate, weight gain, fatigue, slowed heart rate, depression, constipation, memory problems, and lethargy.

– A decreased ability to adapt to cold stress • Common Hypothyroid Disorders: Cretinism, myxedema, simple goiter, and Hashimoto’s

disease.

• Cretinism (infant form): – Occurs during infancy – decreased thyroid hormone production in

infancy results in a lack of skeletal and nervous system development – Symptoms include dwarfism, severe mental retardation, and thickened

facial features. Child has thick tongue and neck – Not usually present in new born due to thyroid hormones from mother – Normal development occurs if thyroid hormones are administered early

(within first month)

• Myxedema (adult form): – Occurs in adulthood - decreased thyroid hormone

production in adults results in accumulation of mucoproteins and fluid in subcutaneous connective tissue. Term myxedema refers to puffy appearance due to hypothyoidism in adults.

– Physical changes include edema of the hands, feet, and face with distinctive facial swellings including swelling of the lips, nose and tissues around the eyes.

– Slow heart rate, low body temperature, muscular weakness and general lethargy, hair falling out.

– Oral thyroid hormones reduce the symptoms • Simple Goiter

– Enlargement of the thyroid gland caused by insufficient iodine

– Inadequate iodine intake causes a decrease in thyroid hormone production which stimulates the anterior pituitary to secrete TSH.

– Increased TSH results in an enlargement of the thyroid gland.

• Hashimoto’s disease:

– An autoimmune disorder where the person’s immune system attacks their thyroid gland.

• Detected clinically by looking for these antibodies in the blood.

• More common in women than men.

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– Hashimoto's disease is the most common cause of hypothyroidism in the United States.

• The signs and symptoms are mainly those of an underactive thyroid gland (hypothyroidism)

• Treatment with thyroid hormone replacement such as synthetic thyroid hormone (levothyroxine).

Hypersecretion of Thyroid Hormone

• Hyperthyroidism – Increased production of thyroid hormones cause increased metabolic rate, heart rate,

weight loss, sweating, and nervousness. • Graves Disease

– An autoimmune disorder in which antibodies mimic the action of TSH by binding to the same receptors, but are not regulated by negative feedback controls.

• Thyroid gland is constantly stimulated to grow and produce excess thyroid hormones

• Signs are similar to hyperthyroidism and can include a goiter and exopthalamus, which is protrusion of the eyes caused by edema behind the eyes.

• Treated by surgical removal of part of the

thyroid gland or to use drugs that block the synthesis of thyroid hormone