Receptors and Cell Signaling

What are the major cell responses to Signaling?

1. differentiation

2. proliferation

3. movement

4. change in energy metabolism

5. cell death

What are the 3 major ways in which there is signaling abnormalities? Examples and/or explanation

Signal hypersensivitiy

overproduction of signal

lack of signaling regulation

signal insensity

lack of signal detection (receptor)

deficient intracellular signaling pathway

interference

Lack of chemical signals

hypothyroidism

certain female infertility

type 1 diabiates

What are the four main types of Signaling?

contact
autocrine
paracrine
endocrine

What are the two ways in which contact signaling can occur

touching the receptors or through gap junctions

In paracrine signaling, what are the two types of signal molecules. Compare and contrast them. Give examples.

Chemical signals: short lived, not a lot produced, receptor high affinity Ex: cytokines

Neurotransmitor: very short lived, lots of produced, receptor low affinity:

What type of signaling involves prostaglandis?

autocrine; low [], short halflife, high affinity receptors

Describe the properties of endocrine signaling

long lasting, highly dilluted, high affinity, produced by endocrine glands; usually bounded by carriers

Describe the signal, signal detection, conversion of signal and regulation of the neuromuscular junction

signal: AcH

Detection: skeletal muscle: nicotinic receptor;

heart muscle: muscarinic receptor

in skeletal muscle: Na+/K+ (Na in, K out); in heart: K+ channel (decrease contractility of heart)

regulation: AcH estorases

Describe the pathology and treatment of Myasthenia Gravis

Myasthenia gravis are autoimmune disorder where antibodies attack the Nicotinic receptors (or MuSK receptors). This leads to AcH having almost nowhere to bind because these receptors are getting internalized and can’t bind to AcH. This produces muscle weakness/fatique.

Treatment: AcH estorase inhibitor. By inhibiting the enzyme that destroys AcH, this compensates for the lower number of receptors

Describe the pathology and treatment of organophosphates on AcH signaling

Organophosphates such as insectiside and nerve gases (sarin, VX) inhibit AcH Estorase. This makes too much AcH, leading to abnormality in contraction/relaxation of muscles. This is most dangerous in the heart bc can lead to death.

Treatment: Block AcH receptors such as atropine (muscarinic AcH receptor antagonist)

What are the five types of chemical signals. Where are they produced and what are they made up of?

Hormones: endocrine cell

amino acids

peptides

proteins

steroid

vitamin d3, retinoic acid

Neurotransmittor: nervous system

neuropeptides

amino acids or derivatives

Eioscanoids: arachidonic acid

arachidonic acid derivatives

Cytokines: by immune system

proteins

Growthfactors: regulates cell differentiation/proliferation

proteins

Which chemical signals are water insoluble? What is the mechanistic difference between hydro phobic/philic molecules

thyroid hormones, steroid hormones, vitamin D3

Hydrophobic can go through cell membrane (except for Vitamin D3 which requires a transporter, either specific or albumin)

What are the type 1/3 nuclear hormones and describe their general signal pathway?

What are the type 2 nuclear hormones?

1/3: nuclear hormones receptors are bounded by heatshock protein in cytosol. the hydrophobic hormones cross through cell membrane and removes the heatshock protein by binding to receptor. receptor dimerize then goes to nucleus for transcription with the help of coactivators. This is because the receptors themselves are transcription factors.

EX: Cortisol, Aldosterone, Progesterone, Testosterone; type 3 = estradiol

2: these receptors are already in the receptor and dimerized in nuclus. But bound to a corepressor. These hormones bind and release these corepressors by replacing them with a coactivator. receptors then help with transcription (they are transcription factors)

Ex: Retinoic acid, vitamin D3, thyroid hormone, fatty acidss

What is dexamethasone?

anti-inflammatory steroid drug that acts through the type 1/3 nuclear pathway (30 times more powerful then cortisol)

What is thizolidinediones (TZDs)

medicine that activates a fatty acid receptor (ppary) that increases insulin secretion. treatment for type 2

Describe the Nitric Oxide (NO) signaling. What 3 drugs utlize this mechanism and for what?

NO can pass through the cell membrane and attach to guanine cyclase which activates cGMP which then create a transduction. important for vasodilation

nitroglycerin, nitroprusside, hydroxyurea

What are the three types of Cell Surface Receptors

ion channel-linked receptor

G-protein-linked receptor

enzyme-enzyme linked receptor

What does ion channel-linked receptors convert? Example?

chemical signal to electronic signal;

ex: nicotinic AcH receptors

Describe the structure of G-proteins.

What are the 5 types of G-proteins, describe them

it has 7 transmembrane domain, with a heterotrimeric G-protein

Adrenergic
family of receptores (a1,a2,b1,b2,b3)

has effects on heart rate, smooth muscle contraction, metabolism

used in medicine (beta blockers for cardiac arrhythmias)

Glucagon

mediates glucagon effect when fasting

Muscarinic acH

regulate heart rate

Rhodopsin

sensing light in rods/cones

Dopamine Receptors

major pharmaceutical target in diseases like parkinson, schizophrenia, ADD

Describe the effects, agonist, and antagonist of the adenosine receptors

What does adenosine do when bind to its receptor?

What receptor does theophylline have less activity on?

What is another weaker AR antagonist?

A1: decreases heart rate

A2a: decrease dopamine, decreases CNS excitement, coronary artery vasodilation

A2b: bronchospasm

A3: prevent cardiac ischemia; relaxation of cardiac muscles; decreases neutrophile degranulation and smooth muscle contraction

agonist: adenosine; antagonist: for all = caffeine; for all except A3 =

theophylline

Adenosine is a ligand for ARs; it slows down heart and antiarrhythmic properties and cardioprotective effects

theophylline has less activity on A3 then A1 or A2

theobromine

What are some examples of ligands that bind to enzyme/enzyme receptors

insulin, growthfactors receptors, interleukens, integrins

Describe the difference between kinases/phosphorylases

kinase = adds phosphate

phosphorylase = removes phosphate

Describe the pathway in which glucagon can generate glycogen degradation

glucagon attach to g protein, activates adenyl cyclase and PKA which phosphorylate glycogensynthesis (inactivates) and phosphorylase kinase. This phosphoatase glycogen phosphorylase which leads to glycogen degradation.

What are the five secondary messengers

cAMP, cGMP, Ca2+, DAG, IP3

Describe the enzyme regulation and second messenger affected by these G alpha subunits:

Gs

Gi

Gq

Gt

Gs: increases adenyl cyclase; Increase cAMP

Gi: decreases adenyl cyclase: Decreases cAMP

Gq: increases phospholipase CB: increase Ca, DAG, IP3

Gt: decreases phosphodiesterase; decrease cGMP

Describe how G-proteins could stimulate or inhibit cAMP production

both pathways are relatively the same. Both transduce the signal via the alpha subunit

both G-proteins (Gs,Gi) are bounded by a ligand.

the alpha subunit is currently holding a gdp and dissociates with its beta-gamma subunit.

the alpha subunit then has a gtp (actual process is more complicated but this is what it says in the slides).

Alpha subunit then binds to adenyl cyclase. Then the action of the g protein is initiated (either inhibit or stimulate adenyl cyclase).

cAMP then activates PKA or not if adenyl cyclase is inhibited

Then, both Gs and Gi have an autohydrolysis of GTP to GDP; effectively acting as an intrinsic stop watch. AFter which, the alpha subunit finds its beta/gamma

How does cholera interact with G-proteins;
How does pertussi toxin interact with G-proteins:

What is a common disease caused by pertussi?

Cholera: adp-ribosynate the active Gs, thereby never turning it off (because GTP can’t be hydrolyzed) which increases cAMP. This leads to dehydration as water secretion and salt into intestinal lumen is unstopped

Pertussis: ADP-ribosynate the inactive Gi, thereby it could never turning on. This allows adenyl cyclase to never be turned off, thereby increasing cAMP. This leads to increased mucus production in airway. AKA whooping cough

How does cAMP regulate PKA

PKA has four subunits (2 catalytic, 2 regulatory). cAMP binds to PKA which causes its dissociation from the regulatory units. then it can phosphorylate stuff.

List out the alpha subunits, secondary messengers, typical locations and effects of these ADRENERGIC receptors:

a1:

a2:

b1:

b2:

a1: Gq; Ca, DAG, IP3; vasoconstriction and dilation of pupils;

vascular smooth msucle, myocardial muscle, visceral smooth muscle, liver

a2: Gi; cAMP; decrease insulin, decrease neurotransmitter

CNA, beta cells

B1: Gs; cAMP; increase heart rate, renin, lipolysis

myocardial cells, JG cells (kidneys), adipocytes

B2: vasodilation, glycogen metabolism, glycogenolysis, bronchodilation, relaxation of uterine smooth muscle

vascular/visceral smooth muscles, skeletal muscle, liver

Summarize these molecules’ effect in heart rate regulation by receptor used, Galpha subunit, mechanism (secondary messenger affected), and heart rate

acetylcholine:

epinepherine:

adenosine:

AcH: muscarinic receptor, Gi,alpha; Decrease cAMP, opens K+ channel; heart rate decreases

epinepherine: b1 receptor, Gs,alpha; increases cAMP, heart rate increases

Adenosin: adenosine receptor, Gi,alpha; decreases cAMP, heart rate decreases

what is caffeine an antagonist of? What does it do?

adenosine, speeds up heart rate

For enzymes receptors or enzyme-linked receptors to activate, what do they have to do first? What happens next?

dimerize, then add phosphate to receptor and bind protein (signal transducer protein)

For these enzyme/enzyme-linked receptors, Describe its pathway and what molecule is the ligand

JAK-STAT

Serine threonine

tyrosine Kinase

Jak-stat: cytokines; ligand binds, dimerizes, JAK binds (tyrosine kinase), phosphorylation of JAK and receptor, STAT binds, phosphorylation, gene transcription regulation

Serine threonin: growth factor B; ligand binds to type 2 receptor, dimerize, type 2 phosphorylate type 1, SMAD gets phosphorylated, gene transcription regulation

tyrosine Kinase: insulin and growth factor; ligand binds, dimerize, phosphorylation of each other; adaptor binds and phosphorylate proteins

What are the advantages and disadvantages of modifying intracellular signaling pathways to solve diseases? Example

advantage: could find alternative path away from a defective one

disadvantage: could interfere with other signaling pathways

Ex: one treatment of diabetes type 2; activates PPAR (perixosome proliferator activated receptor); this induce transcription of genes for glucose metabolism

List five methods in which signal transduction can be regulated

Signal could be destroyed (AcH esterase)

Signal synthesis could be modified (negative feedback loop)

Functional number of receptors could be changed (endocytosis or phosphorylation)

secondary messenger regulator (phosphodiesterase destroys cAMP,cGMP

reverse kinases (phosphatases)

Describe the pathway of rhodopsin

light activate rhodopsin (receptor) activates the g-protein transducin; this g protein activates phosphodiesterase which cleaves cGMP to GMP; this closes cGMP-gated ion channels

Why are muscarinic AcH receptors weird?

its activating subunit is beta-gama; there are no secondary messengers

Explain how the pathway for thyroid hormone secretion is regulated

hypothalamus —> TSH releasing factor —> ant. pit. gland —> TSH —> thyroid gland —> thyroid hormone; thyroid hormone negatively regulates the hypothalamus and ant. pit. gland to not release TSH/TSH releasing factor

What is Graves disease?

when autoantibodies stimulate TSH receptors in the thyroid gland → increasing thyroid hormone production. This downregulates TSH and TSH releasing hormone but thyroid hormone runs loose!