Adv Pathophysiology Unit 1: Cell, Gene, Inflamm, Immune ...people.musc.edu/~decristc/Adv Patho/Unit 1 cell gene inflamm immu… · Receptor theory, cytokines, spare receptors . 2

Adv Pathophysiology Unit 1: Cell, Gene, Inflamm, Immune Page 1 of 24

File: advpatho_unit1_5receptor.pdf Source: C. DeCristofaro, MD

Learning Objectives for this file: 1. Receptor theory, cytokines, spare receptors 2. Receptor types and second messengers 3. Introduce RAS



CELLULAR RECEPTORS: • Protein molecules on cell membrane, in cytoplasm, on nuclear membrane, on DNA, • These receptors can recognize and bind LIGANDS

o A Ligand is any substance that can bind to a receptor o These ligands have different functions

Some are “messengers” such as hormones & neurotransmitters They could also be drugs, infectious agents, volatiles (gases), antigens Some involved with “second messenger systems” where the original

chemical messenger creates a SECOND chemical inside the cell that does the actual work of changing the cell’s physiology

Typical cell membrane with embedded proteins & glycoproteins, many of which serve as receptors.



RECEPTOR CONCEPTS: Receptors & Ligands: • Are endogenous molecules — i.e. synthesized by cells – thus, your receptors are

determined by your genome (DNA) • They are found on cell membranes, in cytoplasm, on DNA. • Most receptors are proteins (or glycoproteins) that form highly specific 3-D shapes

(configuration) having "pockets" that provide a highly selective ligand affinity o they are usually located on the cell membrane or in the cytoplasm (some on nuclear

membrane or the DNA). • Types of receptors include:

o regulatory proteins o enzymes (function as receptors when ligand binding) o transport proteins o structural proteins.

• Receptor Functions: o They bind other substances that are called ligands to change activity of the cell o They serve as sites for cellular attachment (e.g. to allow viruses to adsorb and enter

cells) o They aid in chemotaxis by serving as adhesion molecules (receptors on the cells

that assist cell movement usually in response to cytokines)(e.g. for inflammatory cells) • Ligands:

o chemicals that can fit into the 3D space of a receptor. o Endogenous (chemicals made inside the body, such as hormones) -- OR – o Exogenous (from the outside, e.g. drugs)

Ligand binding: • causes a change in the receptor that is actually a change in its physical shape (a

conformational change) that is called receptor activation (turning on) • what happens with activation:

o may be coupled to a sequence of steps that activates an effector molecule inside the cell (which actually causes the final biologic effect)

o may open up ion channels (allowing flow of ions through the membrane), o may activate an enzyme that will affect intracellular chemicals. Usually this is an

enzyme called a kinase, that activates other cellular molecules by phosphorylation. o may activate enzymes to create another molecule called a "second messenger"

that will itself affect the cell's activity. (In this case, think of the ligand as the "first messenger.")

o complex of ligand+receptor may travel to the nucleus to turn on genetic transcription Receptor variety: • all cells have many receptors • research & development of new drugs often targets receptors & enzyme systems • the more we know about basic science, we now have more therapeutic targets for

pharmacologic interventions



Agonist & Antagonist: • an agonist substance will activate a receptor (turns on) • an antagonist substance will prevent receptor activation

o may physically block the receptor so the ligand can’t get into the receptor site o or, affects receptor in other ways that will prevent its activation

• Clinical correlate: o many drugs exert their pharmacologic action via receptor activation or inactivation

(blocking, degradation). o The muscle paralyzing effects of succinylcholine occur because this drug competes

for binding sites with the endogenous agonist acetylcholine (ACh), thus preventing normal depolarization of muscle cells.

o This is useful to induce surgical paralysis for anesthesia and intubation. Inert Binding Sites: • Ligands can bind here, but do not change the system/cell physiology. • Albumin: a large protein, made in the liver, circulating in blood plasma.

o This can bind drugs in the vascular space, and there are no direct drug effects due to this binding.

o However, drug activity is reduced due to lack of freely circulating drug (bioavailable) • Thyroglobulin: binds thyroid hormone (thyroxine).

o This is another large protein that is made in the liver and circulates in blood plasma. o Different amounts of TG are made under different circumstances, affecting available

thyroid hormone for cells (e.g. estrogen changes the amount of TG and TG binding sites).

Ligand Affinity: • the affinity of a ligand (or drug) reflects its strength of bonding to its specific receptor. • A low affinity ligand/drug dissociates from its receptor more easily & quickly, creating a more

reversible effect.



What are “Second Messenger” systems? • receptors on the cell membrane must somehow create changes inside the cell • the receptor is said to “transducer” their activation into effects within the cell • the interaction with the receptor results in the formation of another (second) chemical

o the first ligand (that binds to the cell membrane receptor and activates it) is the “first messenger”

o the chemical created inside the cell is the “second messenger” – this is what the cell responds to

• Note that (as always) the ligand can be exogenous (come from outside the body, like a drug) or endogenous (created within the body, like a hormone)

• Clinical correlate – therapeutic targets using drugs: o We can increase receptor activity using receptor agonist drugs o We can increase this activity by inhibiting enzymes that degrade messengers o We can reduce receptor activity with receptor antagonist drugs (blockers)



PHYSIOLOGIC RECEPTOR ACTIVITY: • Usually this is linked to THE NUMBER OF RECEPTORS OCCUPIED on a particular • Cells have huge amounts of receptors • once a certain number are occupied, this yields the maximal effect. • The occupation of receptor site is coupled to the activation of the final effector molecule,

which yields the ligand bindng effect. Spare receptors and receptor SENSITIVITY: 1. SPARE RECEPTORS:

• the more receptors, the more statistical "hits" of ligand and receptor. o there is greater receptor sensitivity

• This can also be thought of as increased “receptor density” o an increase in the number of receptor proteins physically located in the cell

• Another aspect of increased spare receptors is how the receptor “behaves” o the increased "spare activity" may be due to the fact that once a receptor is

occupied, the agonist effect is longer lasting that the actual binding/occupying time ("temporal spare receptors").

2. CHANGING RECEPTOR SENSITIVITY:

• Up regulation (increasing receptor sensitivity): o Cells can increase the number of available receptors by synthesizing more

receptors, or reducing destruction of old receptors. o Clinical example:

losing weight or eating a low-fat diet will reduce the amount of cholesterol in the liver; the liver now up-regulates (increases) the number of hepatocyte receptors for HDL-C and increases reverse cholesterol transport (clearing the blood of LDL-C)

statin anti-cholesterol drugs also do this, and by will cause the liver to up-regulate its receptors, clearing more cholesterol from the bloodstream, thus reducing patient's serum cholesterol.

• Down regulation (reducing sensitivity; making cell insensitive); o cell synthesizes less receptors, or increases endocytosis of existing cell

receptors to destroy old receptors. o Desensitization: With almost any hormone, large continuous amounts of

circulating hormone will cause down-regulation, almost like the cell "defending" itself against this onslaught of ligand.

o Clinical example: insulin resistance (metabolic syndrome, MetSyn) • obesity causes more "space" between receptors, thus reducing the

number of insulin "hits" and reducing cell's sensitivity to insulin. Weight loss reverses this effect.

• increased circulating insulin causes adipose cells to destroy insulin receptors by endocytosis, making the cell less sensitive to circulating isulin (Insulin Resistance Syndrome, or “IRS”)

• Overall, either/both obesity and/or hyperinsulinemia worsens IRS



SECOND MESSENGER ACTIONS & INTERACTIONS: • different second messengers may oppose each other's actions, or work together. • Reversible phosphorylation of various substrates (chemicals in the cell) is a common method

of achieving second messenger effects (action of enzymes called kinases). • Although the second messenger may be the same (e.g. cAMP), the action that occurs

in that cell is due to where the cell is located (what organ, what tissue bed) and the function of that cell!!

PHYSIOLOGIC ANTAGONISTS & METABOLIC REGULATION:

• opposing processes keeps the balance Activation of receptors: • there are many different ligands binding to their own receptors on the same cell, causing

opposing effects on the cellular metabolism. • Each cell has thousands of different receptors on the cell membrane and in the cytoplasm. Homeostasis: • physiologic pathways are balanced with separate pathways that "cancel each other out" • the overall biologic effect is to maintain steady-state homeostasis. • Therefore, two different agonists with different receptors and different (separate) biologic

effects may cancel each other out, or "antagonize" each other (due to activation of two opposing physiologic pathways).

Example: cardiac muscle in the heart has opposing receptors – which is dominant? • sympathetic nervous system ligands (epinephrine — raise the heart rate) • parasympathetic ligands (acetylcholine — lowers the heart rate).



OVERALL IDEA OF RECEPTOR ACTIVITY



RECEPTORS FORMING TRANSCRIPTION FACTORS: What ligands use these? • They lipid soluble (lipophilic) • They pass THROUGH the cell membrane to interact with INTRA-cytoplasmic receptors

(receptors INSIDE the cell) • They include hormones:

o sterol (steroid) hormones o thyroid hormone o vitamin D (fat soluble vitamin)

• Activity – forming TRANSCRIPTION FACTORS: o They pass through the cell membrane and bind to INTRA-cytoplasmic receptors o The receptor-ligand complex is called a transcription factor o These now travel to the NUCLEUS of the cell and interact with nuclear receptors o Since they interact with nuclear receptors, they are also called nuclear

transcription factors • Nuclear receptors:

o affect DNA transcription o These nuclear receptors are often called PPARs o Nuclear transcription factors bind to these nuclear receptors with zinc fingers

and activate transcription proteins o Examples:

• STAT transcription proteins activated by colony stimulating factors (growth factors) in bone marrow

• effects of lymphocyte/macrophage cytokines on other cells in the immune response

• drugs newer diabetes drugs, the TZDs, turn on PPARs!! (improve insulin sensitivity)

Number 2 shows the hormone-receptor complex,also called a transcription factor. This travels to the nucleus to stimulate transcription by disinhibiting the DNA (removing heat-shock protein). The new proteins that are made by transcription can be any type of protein. For example: • new enzymes driving metabolic

pathways • special proteins (e.g. pigment) • structural proteins, receptors



STEROL HORMONES: • based on cholesterol chemistry and lipid soluble (lipophilic) • Ligand action in the cytoplasm: binds with cytoplasmic receptors forming a hormone-

receptor complex which is also called a transcription factor • Nuclear action:

o the transcription factor goes to the cell nucleus to activate the DNA to cause transcription of new proteins, altering cell physiology

o this is due to disinhibition (removal of inhibition) of DNA transcription o sometimes this occurs by removal of a protein associated with DNA called “heat

shock protein, hsp90) that has been inhibiting DNA transcription • Action on cell metabolism:

o It takes LONGER for the action to occur (transcription & translation take at least 30 minutes) – BUT the action will probably be LONGER ACTING since the final cellular products last for hours to days

o Action of these hormones also relies on the number & sensitivity of the intracytoplasmic receptors.

o Action on DNA transcription may also affect upregulation or downregulation of cell receptors

o Example: cortisols upregulate the number of beta-2 receptors in lung, making lung more sensitive to circulating epinephrine for improved bronchodilatation

More below on STEROL HORMONE biosynthesis…



Steroid (Sterol) hormone biosynthesis: It all starts with CHOLESTEROL, acted upon by multiple enzymes to create pathways leading to the STEROL HORMONES that have a LIPID chemistry. CHOLESTEROL (dietary or made de novo) PREGNENOLONE PROGESTERONE 17-alpha-OH-PREGENENOLONE 17-alpha-OH-PROGESTERONE DEHYDROEPIANDEROSTERONE (DHEA) 11-desoxy- CORTICOSTERONE 11-desoxy-CORTISOL ANDROSTENEDIONE 17-keto-STEROIDS CORTICOSTERONE CORTISOL ESTRONE TESTOSTERONE ALDOSTERONE CORTISONE ESTRADIOL Di-hydro-TESTOSTERONE Mineralocorticoids Glucocorticoids Female Sex Hormones Male Sex Hormones Since they arise from cholesterol, they are soluble in the cell membrane, which is made from phospholipid (which is also made from cholesterol). That is why the steroid hormones can travel right through the cell membrane to interact with the intra-cytoplasmic receptors for these hormones.



NITRIC OXIDE (NO) GAS AND cyclicGMP (cGMP) FORMATION & ACTION: • NO used to be called endothelial derived relaxing factor (EDRF) • this is a lipid-soluble gas

o made by capillary endothelial cells and some parasympathetic neurons o causes vasodilatation of blood vessels by relaxation of smooth muscle

Mechanism – a second messenger system using cGMP: • Process:

o NO binds to intracytoplasmic enzyme (guanylyl cyclase, GC) to produce the secondary messenger cyclic-GMP (cGMP)

o cGMP causes dephosphorylation of myosin light chains and resultant muscle relaxation with associated vascular vasodilatation

o The cGMP is then degraded by Phosphodiesterase enzymes (PDEs). • Drug correlate:

o Drugs that turn into NO: all the nitrates (e.g. nitroglycerin, nitroprusside) are converted to NO in the

body & are therefore vasodilators by action on vascular smooth muscle smooth muscle relaxation results in blood vessel vasodilatation

o Drugs that inhibit PDE (PDEIs): enhance cGMP activity by inhibiting a subtype PDE enzyme (PDE5) include Sildendafil (Viagra) and other drugs for erectile dysfunction improve strength & duration of erection by inhibiting the degrading enzyme and

allow cGMP to last longer Drug-drug interaction: since cGMP activity is also induced by nitrate drugs,

this is WHY you should NOT take PDE5 inhibitors within 24 hours of taking a nitrate drug due to additive effects of overwhelming vasodilatation and possible severe hypotension.

o Selectivity of PDEI drugs: remember about isoenzymes – enzymes exist in multiple “isomer” forms, thus there are subtypes of PDEs in the body Your therapeutic target for erectile vascular tissue is PDE5, and you want

PDE5 inhibition (PDE5i) and not affect the other PDE enzymes. Newer drugs that compete with sildenafil in the market are vardenafil (Levitra)

and tadalafil (Cialis) which claim to be more selective for PDE5. Pharmacology assays determine the “selectivity ratio” One drug side effect for sildenafil & vardenafil is due to the interaction with

PDE6 that can cause visual symptoms (a “blue tinge” to the vision).



NOW – THE NON-LIPID SOLUBLE (NON-LIPOPHILIC) LIGANDS • These are also called hydrophilic • These are usually based on protein chemistry • They require receptors based in the cell membrane – they can interact with the cell

membrane receptors, since they CANNOT pass through the cell membrane to interact with intra-cytoplasmic receptors

• They will cause effects in the cell through indirect means since they can’t pass directly into the cell

CELL MEMBRANE RECEPTORS FOR NON-LIPID SOLUBLE LIGANDS (PROTEINS): • interact with protein ligands or any ligand that CANNOT PASS through the cell membrane • Different ways these types of receptors act based on the type of receptor • Different types of cell-membrane receptors:

o G-protein receptors that create second messengers cAMP or DAG-IP3 o transmembrane receptors o ligand gated-ion channel receptors

HOW PROTEIN HORMONES WORK WITH SECOND MESSENGER SYSTEM RECEPTORS



"G" PROTEIN RECEPTORS & SECOND MESSENGERS SYSTEMS: • the most common in the body • these receptors create second messengers • (remember the initial protein ligand is the ”first” messenger, and another chemical is created

in the cell to do the actual job) o cAMP (cyclic-AMP) second messenger system (and cGMP)

OR o DAG-IP3 second messenger system

Structure & function of G-protein receptors: • receptors look like "serpents" (winding in and out of the cell membrane multiple times) &

called "serpentine receptors." • Ligand binding to the receptor site on the outside cell membrane activates a "G" protein on

the cytoplasmic side of the membrane. • On the cytoplasmic side, the G protein releases GDP & accepts GTP, forming G-GTP, which

is the active form of the G protein). • G-GTP, in turn, activates the final effector mechanism production of an intracellular

second messenger. Examples: • this type of receptor is includes the visual photon receptors (rods & cones) • olfactory epithelium mucosal odorant receptors • serotonin receptors • many peptide hormone receptors (glucagon). Receptor Desensitization: ****clinically relevant • if the cell is flooded with a lot of ligand, then the cell will react by causing a reversible

reduction in receptor response • “self protection” of the cell against too much ligand • this is used in pharmacologic management of hormonal conditions!! Let’s look BELOW at these two second messengers of the G-protein receptors…



cAMP (and cGMP): the little “c” stands for the chemical term “cyclic” • Cytoplasmic cAMP stimulates multiple cellular enzyme systems mainly by activating

protein kinases (phosphorylating enzymes), that phosphorylate proteins (enzymes) to activate them.

• cAMP action is specific by ONLY virtue of what organ tissue it is working in and the unique enzymes present within those tissues cells.

• cAMP: the most common second messenger in the body o the ligand first creates GDP when it activates the cell membrane receptor o the GDP then activates an enzyme in the cell membrane called adenyl cyclase o this enzyme breaks down (converts) ATP to cyclic AMP (cAMP)

• Adenyl cyclase enzyme causes reaction: ATP 2Pi + cAMP

o cAMP has various actions in the cell (usually stimulates metabolism of the cell by activating enzymes like protein kinases)

o degradation of cAMP to 5-AMP by enzymes called cyclic nucleotide phosphodiesterases (PDEs)

o the PDEs exist in multiple isoforms (e.g. PDE1, PDE2, etc.) • Examples of ligands using cAMP:

o catecholamines (epinephrine, norepinephrine), Acetylcholine (muscarinic receptors, eicosanoids (serotonin, prostaglandins), olfactory odorants, photons (visual receptors), ACTH, MSH, FSH, LH, PTH, thyrotropin

o Examples: • in the liver, action is on glycogen metabolism; • in adipocytes, action is on lipases (release FFA); • in muscle, myosin kinase is involved in smooth muscle relaxation activity

• Drug correlates for cAMP: o PDEIs: inhibition of PDE (PDEIs) stops degradation of cAMP

• include drugs like caffeine, theophylline, methylxanthines • cAMP concentration remains high longer and works longer • smooth muscle relaxation in bronchial lung tissue bronchodilatation

o Opioids inhibit adenyl cyclase: cell can’t make cAMP opioids cause bradycardia.



Another picture of the cAMP second messenger system: Outside the cell ------------- ------CELL MEMBRANE-------------- Inside the cell degraded by phosphodiesterase enzyme (PDE)

LIGAND (molecule that binds with receptor) is the first messenger

RECEPTOR in cell membrane

Formation of SECOND MESSENGER molecule (cyclic AMP, cAMP)

Inactive cAMP – changes in cell physiology end once this substance is gone



(The other second G-protein receptor system ) DAG-IP3 Second Messenger System: • What kinds of ligands use this receptor?

o non-lipophilic (hydrophilic) ligands that are not soluble in the cell membrane phospholipid (these are usually protein ligands)

o stopped at the cell membrane & interact with cell membrane “G-protein receptors” o receptor activation creates second messengers o these include diaglycerol-inositol-tri-P also called DAG-IP3 and DAG-PIP

• Process of creating second messenger DAG-IP3: o cell membrane phospholipid is broken down DAG-IP3 o IP3: causes Ca+ release from cytoplasmic storage areas; this provides the

Calcium needed for the DAG to work o DAG: stimulates protein-kinase-C (PKC) in the cell (needs Ca+2 to work).

• Overall effect: o Increased Ca+ in the cell AND activation of kinase enzymes

• Degradation to end activity: o the DAG is either turned back into phospholipid or arachidonic acid; o the IP3 is inactivated in the cytoplasm; o Ca+ that has been released is pumped back into storage sites by cellular

pumps. • Clinical:

o Lithium drug for manic-depressive illness o activation and modulation of smooth muscle (cadmodulin system) o protein kinases (phosphorylate proteins, & activate enzymes)



Another picture of G-PROTEIN LINKED DAG-IP3 SECOND MESSENGER SYSTEM

LIGAND

ECF (outside cell)

G-PROTEIN RECEPTOR CELL MEMBRANE CELL MEMBRANE PHOSPHOLIPID Phospholipase C (PLC) enzyme breaks phospholipid into ICF (inside cell)

IP3 increased intracellular Calcium that stimulates cell processes

DAG activates enzyme protein kinase C intracellular phosphorylation stimulates cell processes



TRANSMEMBRANE (PROTEIN KINASE ENZYME) RECEPTORS : • these will either activate an intracellular enzyme OR create a second messenger • Structure & function:

o these receptors are located in the cell membrane o structurally through & through the cell membrane (from out to in) o two ligands cause a conformational change in this receptor to activate a protein

kinase enzyme that uses ATP energy to create activated proteins and a cellular response

o they have an extracellular area and an intracellular area that work together with receptor activation

o Extracellular domain: the contiguous receptors on top of the cell membrane, outside the cell, are

normally separated by hydrophobic repulsion. binding of the ligand causes a conformational change, allowing these

neighboring receptor molecules to move closer together, which activates the o Intracellular domain:

activation of a cytoplasmic enzyme (e.g. tyrosine kinase) OR creation of a second messenger (e.g. cGMP)

• Clinical: o used by insulin o EGF(epidermal growth factor) o PDGF (platelet derived growth factor) o ANF (atrial natriuretic factor) o TGFB (transforming growth factor-beta).

• Typical degradation of second messenger cGMP: o an example is degradation of cGMP by specific phosphodiesterase (PDE) enzymes o the PDEs exist in multiple isoforms (e.g. PDE1, PDE2, etc)



More pictures of TRANSMEMBRANE ENZYME RECEPTORS

LIGAND (HORMONE OR OTHER CHEMICAL)

Outside the cell ----------------------------------------------------------------------------------- CELL MEMBRANE---------- EXTRACELLULAR DOMAIN OF RECEPTOR

move together & become activated

-----------------------------------------------------------------------------------CELL MEMBRANE----------- INTRACELLULAR DOMAIN OF RECEPTOR (activation of an enzyme) Inside the cell FINAL RESULT: usually, an enzyme of the “kinase” class is activated, that phosphorylates chemicals in the cell to turn on physiologic processes. Other enzyme cascades can also occur, that can stimulate nuclear transcription, or make other chemicals that are “second messengers” inside the cell to also affect enzyme functioning and metabolic biosynthetic pathways.



LIGAND GATED CHANNEL (ION CHANNEL) RECEPTORS: • ligand binds to cell membrane receptor, and activation of the receptor causes ion channels

to open. • This is like a gate opening or closing. What kinds of ligands use this receptor?

o non-lipophilic (hydrophilic) ligands that are not soluble in the cell membrane phospholipid

o they are “stopped” at the cell membrane and so must interact with cell membrane receptor

o agonist effects induce a conformational change in this receptor to OPEN ion channels

• Examples of endogenous substances using this system: o neurotransmitter ligands such as ACh (acetylcholine), GABA (gamma aminobutyric

acid), & excitatory amino acid neurotransmitters (glycine, glutamate, etc) o all synaptic transmitters affect ion channels.



Example: the nicotinic ACh receptor actually opens a central aqueous channel inside the transmembrane receptor that allows Na to enter the cell.



RECEPTOR DYSREGULATION & RECEPTOR DISEASES: Normal change in available spare receptors: • Cells can change the number of receptors available on the cell membrane. • Up-regulation: Increasing receptors requires synthesizing more receptors. • Down-regulation: Reducing receptors requires endocytosis and destruction of old

receptors. Clinical correlates: • in the presence of too much ligand that is continuously present, the cell will down-regulate

the number of receptors (“protecting itself” from overstimulation) • Other ligands may actually exert part of their effect by inducing up-regulation. • Insulin resistance & down regulation:

o with obesity and/or increased circulating insulin (e.g. insulinoma, iatrogenic) the adipose cell destroys receptors by endocytosis, making the cell less sensitive to circulating insulin (insulin resistance in obesity) since there are less available receptors.

o The size of the adipocyte is important here also – the bigger the cell, the larger the cell membrane, pushing the receptors further away from each other and resulting in less statistical hits for the insulin (insulin resistance).

o This can be reversed, when adipocytes shrink in a diabetic who loses weight the receptors come closer together and are effectively more responsive to available insulin, and new receptors may also be synthesized (or at least not destroyed as fast).

• Corticosteroids & up regulation: o cortisols affect cells in many ways. o One way is to up regulate the number of receptors that are available for sympathetic

nervous system ligands (norepinephrine & epinephrine), thus promoting bronchodilatation (combats allergic reactions)

• Genetic Absence of Receptors: o Thyroid resistance: genetic reduction of receptors for thyroid hormone; although

normal to high thyroid hormone levels, they’re clinically hypo-thyroid. o Nephrogenic Diabetes Insipidus: the kidney cells lack receptors for ADH

(vasopressin), so can't regulate reabsorption of water polyuria from diuresis of an abnormally dilute urine.

• Antibodies to Receptors: autoimmune diseases create antibodies that destroy receptors. o Graves disease: antibodies to TSH receptors, causing thyroid dysfunction. o Myasthenia gravis:

destruction of the receptors for Acetylcholine, located on the skeletal muscle. This destruction of the ACh receptor causes lack of normal function of skeletal

muscle cells due to dysfunction of neuro-muscular transmission.



EXAMPLE OF RECEPTORS IN ACTION: the answer to every question is “receptors” (haha from Dr D) An example of a biological system depending on receptor action is the

RENIN-ANGIOTENSIN-ALDOSTERONE-ADH-KININ SYSTEM (RAAAKS) RENIN-ANGIOTENSIN ENZYME ACTIONS ACE'S OTHER JOB (KININ PATH) Action on receptors • ACEIs (ACE inhibitor drugs) reduce formation of Angiotensin-II & allow vasodilating

KININS to be active (overall vasodilatation, reduction in BP). • ARBs (Angiotensin Receptor Blocker) drugs that block the AT1 receptor) also lower

BP. • DRIs (Direct Renin Inhibitor drugs) prevent the action of renin enzyme at the

beginning of the entire pathway • In addition to BP effects, overall effects of interfering with or blocking the RAAAKS

will improve cardiomegaly, heart failure and protect the kidney. If you know how the chemicals act on the receptors, you have all the answers.

Angiotensinogen (inactive, made in

liver) Renin and

other enzymes (e.g. tPA)

Bradykinins Inflammatory and VASODILATING Kinins (in lung &

elsewhere)

Angiotensin-I (not very active) ACE

in lungs and other non-ACE

enzymes (e.g. chymase) Angiotensin-II

Hormone active Degraded Kinins now inactive, balance shifts to vasoconstriction

AT1 Receptor (THE BAD GUY) vasoconstriction, endothelial mitotic effects (accelerated atherosclerosis), release ADH & Aldosterone (salt & water loading), cardiac remodeling (LVH), reno-vascular effects pathologic amounts = HTN, volume loading, cardiomegaly, nephropathy

AT2 Receptor (THE GOOD GUY) vasodilatation (opposite effects from AT2 Receptor)

Documents

Adv Pathophysiology Unit 1: Cell, Gene, Inflamm, Immune ...people.musc.edu/~decristc/Adv Patho/Unit 1 cell gene inflamm immu… · Receptor theory, cytokines, spare receptors . 2