Receptors and cell signaling

What area some major cell responses to signal?

Proliferation, movement, differentiation, altered metabolic activity, and cell death

What an example of lack of chemical signals?

Type 1 diabetes ie no insulin being produced

What are some examples to insensitivity to signals?

Type II DM ie insulin receptor not as sensation to the same insulin signals.

What about hyper response to a signal

HTN, cAMP in cholera

What kind of signaling do cytokines take part of?

Paracrine signaling ie signaling between cells who are close to one another.

What king of signaling does prostaglandins take part of. Described the chemical signal and receptor affinity.

Prostagladins take part in autocrine signaling

Chemical signal: low concentrations since the receptor has high affinity.

What are the characteristics of endocrine signaling

Carriers, long half life, slow cell response,

What is the regulation of ACh in the neural muscular junction?

Regulation is done through acetylcholine esterase ie we need to get rid of Ach

What is released with nictonic ACh receptors? What about muscarinic?

Nictonic ACh receptors uses Na/k channels. Ie 3-2-1 NOKIA (Skeletal)

Muscarinic ACh receptors use G proteins to regulate K+ (heart)

What is the consequences of impaired ACh signaling? What is the disease called and what can do do to fix this?

Causes Myasthenia gravis -autoimmune neuromuscular diasese

Mechanism: Autoantibodies —>nicotinic ACh receptors —>insuf signalling

Management: ACh esterase inhibitors —> increase ACh —>more powerful signal

What does Sarin do to ACh? How can we treat this?

Sarin is a organophosphate which irreversibly inhibits ACh esterase

Cause too much ACh which results in contraction impairment (death if in heart)

Management: Atropine (ACh musarnicic receptor antagonist —> calms down signal in heart)

How are water insoluble steroids transported?

Through carrier molecules ie vitamin D3 require albumin

Where are type 1 and 3 nuclear receptors found and what complex are they associated with? What is the anti inflammatory steroid which acts on his pathway?

Localized int he cytosol within HSP

Steroid binding —>HSP shed and receptor dimerized—>goes to nucleus —>transcription regulation via factors

Management: Dexamethasone

Type I: Cortisol aldosterone progesterone testosterone

Type III: Estradiol

What do type II receptor bind to? What is the treatment that acts ont his pathway?

Retinol acid, Vit D3, thyroid hormone, and FAs

Mechanism: in the nucleus in a dimer form —> can’t bind due to corepressor. When hormone binds corepressor traded for coactivator—> turned on

Management: Thiazolidinediones (TZDs) activates FA receptor and increase insulin sensitivity —→ treats T2DM

A patient with type II diabetes comes in, what type II nuclear signal would be used?

They will be using a FA type II receptor which will increase insulin sensitivity via thiazolidinediones (TZDs)

A deficiency in guanylate cyclase causes what? What drugs can we use to treat a NO deficiency?

Guanlate cyclase is activated via NO and generates cGMP (2nd messenger) —>vasodilation

Clinical relevance: If the enzyme is inhibited above then we will has decreased dilation, thus decreased blood throughout the body thus decreased O2 delivery.

Management: nitroglycerin, nitroprusside and hydroxyurea.

give an example of ion Chanel linked receptors

Nictonic ACh receptors

Turns chemical to electrical signals.

What does andreneic receptors regulate?

Heart rate, smooth muscle, metabolism

Examples of drugs include beta blocks to treat cardiac arrhythmias)

If a drug targets domaine receptors what can they treat?

What is an example of enzyme linked receptor, what is the pathway?

Insulin activated enzymes (kinases) which leased to intracellular signaling cascade

What is an example of a enzyme link receptor

Insulin —>act kinases—>intracellular signaling cascade

What the second messengers for G protein linked receptors? What subunit medicates signaling?

CAMP, cGMP, Ca, DAG, IP3

The alpha subunit mediates signalling via the present of GTP (activation) or GDP (inactivation)

A mutation in the associated subunits of G proteins will cause a decreased activation of what type of enzymes?

The second messages wont be able to activate protein kinases thus the kinases wont be able to activate their downstream products.

High concentrations of what activates PKA?

CAMP

What is the affect of Gi and Gs alpha for adenylyl cyclase? How does the concentration of cAMP cause?

The inhibitory subunit: bind to AC and inhibit it —>decreased cAMP—→ decreased PKA

The stimulatory subunit will:

binds to AC activating it —> makes cAMP —> PKA activated

A patient with cholera toxin has what affect on the Gs alpha subunit?

Stimulates the G protein thus is Gs, caused too much cAMP —>high PKA —→phosporilization of proteins —>salts and water from gut —→diarrhea

A patient with pertussis toxin has what affect to the Gi alpha subunit?

Inhibits the Gi thus it will not be able to inhibit AC —> high cAMP —> high PKA —>increase mucus secretion in pathways.

What is an example of an alternative pathway and treatment for Type II DM?

T cells are an example of what kind of signaling?

Contact signal ie makes contact with the target molecule.

Cytokines are an example of what kind of signalling? What is the characteristics of the receptors and chemical signal?

Cytokines are a type of paracrine signalling

Chemical signal: low concentration since the receptor has high affinity

Neurotransmitter: high concentrations as the receptor have low affinity.

What are the characteristics of endocrine signalling? Where are these signal made and how do they move around the body?

Endocrine signalling uses signals produced in the endocrine glands. they have long half lives as they are far from their target and frequently are moved around with carrier as they are not water soluble ie hormones.

What are some examples of ACh esterase inhibitors and what disease do they treat?

pyridostigmine, neostigmine, physostigmine. They increase the amount of ACh treating diseases such as Myasthenia gravis

What are types of chemical signal we can see? Which ones are known for inflammation?

Neurotransmitters

Hormones

Cytokines (inflammation)

Eicosanoids (Arachindoinic acid derivites)

Growth factors

What are examples of G protein linked receptors?

Adrenergic (heart rate, smooth muscle, meta), glucagon (meta), muscarinic (heart rate), rhodopsin (light), dopamine

Epi/norepinephrine receptor deficiency causes what?

Decreased heart rate, smooth muscle contraction , and metabolism

Management: Beta blockers to treat cardia arrhythmias

Dopamine receptor deficiency causes what?

Schizophrenia, Parkinson’s, attention deficit

What is caffeine an antagonist to? How does this work in respect to the affected receptor?

Caffeine is an antagonist to AR, thus if adenosine receptor are inh then heart rate will increase.

What is the differences between AR 1 vs 2A vs 3 receptors?

AR1: Decreased heart rate

AR2A: Heart vasdialition, decrease dopa in CNS, inh of CN excitation

AR3: Cardiac muscle

Ie think about what caffeine has to do with these processses and caffeine’s side effects

A patient know to have deficient alpha G protein subunits, what is the enzyme affected and how does it usually function?

A deficiency of the alpha subunit of the G protein will result in the decreased or increased function of adenylyl cyclase.

This will depend if the G subunit is inhibitory or stimulators.

What is the cAMP dependent PKA made of? What is the mechanism?

Made of 2 catalytic and 2 regulatory subunits

binds cAMP to reg subunits—>disassociated PKA subunits —>activates catalytic subunits

What is an example of lack of chemical signals

Type I DM

What is an example of hypersensitive response

HTN or cAMP in cholera/whooping cough

Via overproductions of signal/ too sensitive of receptor

What are examples of contact signalling?

Cancer and T cell recognition.

What are the differences of chemical and neurotransmitter paracrine signalling in respect to both the signal and receptor

Chemical - low concentration, high affinity receptor

Neurotransmitters - high conce, low affinity receptor

Ie . Signal inversely proportional to the receptor.

What is an example of author inertia signaling and what is the relationship of both signal and receeptor

Prostaglandins - signal in low concentration thus receptor is high affinity

Relation inh by aspirin via COX 1 and 2

What is an example of endocrine signaling and are the characteristics of the signal and receptor

Hormones are released int he blood at very low concentrations so the receptor is is very high affinity. —→ slow cell response.

What is the regulation of the NMJ?

Acetylcholine esterase —→ degrades excess ACh

Too much enzyme = myasthenia gravis

Treated via ACh esterase inhbitors

What are the two types of ACh receptors and where are they found

Nicotinic - skeletal (nictatine stains to the bone) Na/K channel regulated

Musacrinic Ach - (heart is all muscle) G protein link receptors regulate cAMP and K channel

What activates muscle contraction and realxation

Contraction - nictonic (need the skeleton to move)

Relaxation - muscarinic (need muscles to relax)

If a a patient is found with autoantibodies against nictonic ACh receptors, what diseases would this cause?

Myasthenia gravis

** only affects the skeletal muscle and not cardiac

Internalization of receptor = no response.

EWhat is an example of a disease with too much ACh signalling

nerve gases (organophosphate) such as Sarin irreversible inhibits ACh esterase thus too much ACh in muscarinic receptor will relax too much - dead

What ar the 5 types of chemical signals

Neurotransmitters, cytokines, hormones, eicosanoids, growth factors

Exception to hormones: VitD3 and retenioc acid

What are different types of hormones

AA derivative, peptides, proteins, steroids, Vit D3 and retinoic acid

Remember depending on polarity the hormones may need a. A carrier molecule

How is water solubility and the type of signaling relateed

If the hormones are polar and water soluble they will need to bind to a receptor to be brought across through a carrier

If it is non polar and small it an pass through the membrane

What type of receptors bind to HSP and what is the resultant

TType 1 and 3 nuclear receptors used HSP and dimerize when active. They THEN are transported to the nucleus once binding to the hormone. —> transcription factors.

---

zinc and Lucerne zipper found ont he surface of the nucleus.,

What is the main difference between Type 2 hormones when compared to Type 1/3

Already localized in the nucleons as a dimer. When hormone binds coactivaotr replaces repressor —> transcription factors

What is the difference between phophotransferase vs kinase

Kinase phosphate comes from ATP only

What is the difference between enzyme and enzyme linked recepetrs

Enzyme - G proteins

enzyme linked - insulin ie doesn’t use 2nd messagners

What ar the two G protein subunits which increase 2nd messanger? What about decrease?

Gs and q subunits act 2nd messanges. CAMP and DAG/IPS3/Ca respectively

Gi and Gt decreased cAMP and cGMP respectively

Hydrolaization of what deactivates G proteins

GTP —→GDP

What are the hormones that stimulate G s subunits?

Epinephrine, glucagon, ACTH

What are examples of hormones which act on G i subunit

PGE and adenosine.

What is the post translation modification is cholera associated with?

ADP ribosylation caused the Gs subunit to never be deactivated. Increases cAMP then increased PKA causing salt and water flux —>diarrhea

What subunit does pertussis toxin affect?

It affects the Gi subunit, thus the inhibitor cannot work and excess cAMP and PKA activation —> increased mucus

A patient comes in elevated autoantibodies against their Ach receeptor? What disease does this pateint most likely have? What type of Ach receptor does this disease affect?

MG, think autoimmune

Autoantibodies —>nicotinic Ach receptor —> internalization

• Amount of Ach can’t diagnose this as Ach production is not impaired.

• To test we can do a nerve test/ice pack test

• Hypoxia, pitosis, inh breathing via diaphragm are key signs

Management: ACh esterase inh —→ more Ach to compensate for less receptors

---

can be caused by autoantibodies or MuSK(muscle specific kinase)

What happens if a nerve gas is exposed to our pateint, in particular Sarin. What are some symptoms we see and how does this differentiate between Ach receeptors?

Sarin is a nerve gas (organophosphate) —→ irresably binds to Ach estersase —→ too much Ach —> relaxation of heart

***Different response as we are activating a muscarinic receeptor instead of a nicotinic. Causes there to be a depletion of Ach

• To test for this we can test the amount of Ach (different compared to MG where Ach is the same and the receeptors are less)

Management: We need to decrease signaling thus we can inh Ach signaling ie use a muscarinic antagonist (Atropine)

A patient is deficent in guanylate cyclase, what will see a decrease in and what is the physiological changes associated with this?

We will a decrease in cGMP this we will see a decrease in vasodilation

Too much nitroglycerin, nitroprusside, and hydroxyurea can also cause similar symptoms.

What kind of receptor is a nictonic receptor?

It is a ion channel link receptor ie turns chemical signal to electrical ones

What do andrenergic receptors ligands and what do they control? What can we use to manage patients with elevated response of these recepetors?

Epi/norepinephrine are the ligand ie. Think flight or fight.

They regulate HR, smooth muscle contractions and metabolism

What are the 4 type of adenosine recepeptors and how do they differ?

A1: decreased heart rate

A2a Cornary artery vasodilation, decreased dopa in DNA, inh of CNS

A2b : bronchosapm

A3: Muscle relax, smooth muscle contraction, cardio ischemia protection, inh of neutrophils

1 always equals HR

2b a bronchospasm

3 musketeer fighting a pedophile

A = artery and dopA

What type of receptor is a muscarinic Ach receptor

G protein linked

How is PKA acitivated and give an example of downstream affects ie with the degration of glycogen

G protein activated via GTP—→ inh the inh subunit of PKA —>phosphorylase phosphylase kinase (activated) and glycogen synthase(inactivated) —>phosphorylates glycogen phosphylase (active) —> degration of glycogen

What is are the G subunits and how do they differ in they 2nd messanger affect/

Gs —. Increases camp

Gi —>decreases camp

Gq —→ increased DAH, IP3, and Ca —>act phospholipase Cb

Gt —→ decreases cGMP —>act phosphodiesterase

How do decongestant and eye drops in expect to andrenergic signaling? What call of drugs are these apart of?

These act by increasing the vasocontrictive affect of alpha1 adrenergic receptors. These are apart of drugs called Alpha1 andrenergic agonists

We want to constrict the blood vessels in the eye to be able to reduce swelling and redness.

How do we remember what the different andrenergic receptors do?

Use qiss (ie kiss)

alpha 1: Gq increased ca , ip3, and DAG vasoconstriction, dilated pupils

Alpha 2: Gi decrease camp decreased neurotransmitter release and decreased insulin

Beta 1: Gs increase camp increased HR, renin, lypolysis

Beta 2: Gs increase camp occurs in the liver so associated with glycogenolysis and metasbolism, uterus realization, bronchodialaition

Give an example of how a GCPR can alter cGMP levels

Rhodopsin —>act transduction —→ alpha sub act phosphodiesterase —>cGMP to GMP (now 2nd messanger)

Decrease in cGMP close cGMP gated ion channels

What is the exception to G proteins

Muscarinic Ach receeptor are wired because they are activated by the Beta-y subunit and there are no 2nd messagners or kinases

What is the general outline for enzyme or enzyme linked receptor activation

Dimerize Gino —>phosphoylization —> binds to signal transducer proteins

What is the JAK-STAT receptor pathway and how does it differ from other enzyme recepetors?

Used by cytokines —>JAKs associate with receptor —>binds to STATS

SPECIAL: JAKs phosphorylase each other then STAT —>reg of gene transcription

What is the serine threonine kinase receptor pathway and how does it differ?

Uses growth factor beta family

Uses R-same as a signal transducer prtien

DIFFERENT: Type II phosphylates type I which phos Rsmad—>gene regulation

What is the tyrosine kinase pathway and how does it differ?

Many growth factors and insulin —>act MAp kinase, PLCy pathways

DIFFERENT: Also phophorilates each other, uses RAS complex which binds to GDP —> switched for GTP then acitivated

What is Graves’ disease and what is it a prime example of?

Graves disaes is over production of thyroid hormone via the thyroid gland —> causes negative feedback which will decrease the amount of TSH releasing hormone and TSH is released

Hypo release TSH releasing hormone —>ant put release TSH —>thyroid release thyroid hormone which feeds back and inh the hippo and ant put.

How is signaling regulated ie terminated

Destruction of chemical signal or 2nd messanger, decreased synthesis, reverse kinase affects ie phosphataes, red of receptors ie desensitization through phosphorilization or endocytosis removal of them

What is alternative pathway for T2DM?

Activating perixisome proliferator activated receptor (PPAR) —> glucose metabolism upregualtion via genes.

What is PLCy used for

Excess glucose to be stores as glycogen or FAs

What is MAPK used for?

Reg transcription and translation of genes needed for glucose meta

What is Pi 3K used for

GLUT4 —>muscles and adipose tissues