Endocrinology Midterm (Hormone Action)

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These are increased or decreased by hormones

Activity of enzymes

Transcription of genes

Translation of RNA into protein

Secretion of molecules

Rate of mitosis

Rate of cell death/remodeling

Cell permeability/water retention

A hormone can modify

Anything a cell can do...

Several

How many changes can a single hormone typically trigger in a cell?

Their own/unique...Actions of a hormone are specific to a given target cell

Differentiated cells respond to hormones in what way?

Yes

Can a single hormone have many target organs?

Yes

Will a single cell have receptors for many different hormones?

Biochemical changes within the cell

Binding of a hormone to its receptor triggers what?

Increases

A cell's sensitivity to a hormone does what with increasing numbers of receptors for the hormone?

...

Modified amino acids

Peptides

Proteins

Glycoproteins

Steroids

Sterols

Eicosanoids (leukotrienes and prostaglandins)

Half life of a hormone

How long it takes the body to metabolize half of the molecules of a circulating hormone

Seconds to days

Half lives of hormones can be...

How long the hormone is able to act

What is important about a hormone's half-life?

Better/finer

Shorter half lives provider what kind of control of variables?

Saves energy from less hormone synthesis, packaging, and secretion

Longer half lives have these advantages

The shorter the half-life

Hormones made from amino acids, the shorter the chain...

Glycoproteins

These last longer than proteins because the CHO groups protect protein chains from proteases

Variable between specific hormones

Steroid hormone half lives are...

Thyroxin

This is the circulating form of thyroid hormone (not active)

Has a half-life of six days

Six days

Half life of thyroxin is what?

No

Is size the determining factor for steroid, sterol, and thyroid hormone half lives?

Molecular structure

What determines whether a hormone can cross the cell membrane?

Determines whether a hormone acts by binding outside the cell membrane or by entering and binding inside the cell

Lipid solubility

This factor determines whether hormones can cross the cell membrane

Allows steroids, sterols, and thyroid homrones to cross cell membrane and bind to internal receptors

Non-polar

In order to be liquid soluble a molecule must be what?

Amino acid derivatives, proteins, glycoproteins

These hormones are polar

Can't cross cell membrane; must bind to membrane-bound receptors on the outside of the cell

Work through molecules on the inside of the cell such as G proteins, second messenger systems, and other enzymes

No

Is size a determining factor in a cells ability to cross a membrane?

Catecholamines

These are smaller than steroids but cannot cross the cell membrane (size doesn't ability to do this)

G proteins, Second Messenger Systems, other enzymes

These are used by polar hormones (AA's, proteins, glycoproteins) to affect cells

Steroid hormone action

This crosses the cell membrane and enters the cell nucleus

Binds to specific receptor proteins

Formation of a ________-receptor complex changes shape of protein receptor

This complex binds to recognition/acceptor sites on the DNA (Hormone response elements)

This changes the configuration of the DNA strands and influences availability of specific genes for transcription to mRNA

Adrenal cortical hormones

These hormones are steroids

They may bind to cytoplasmic receptors before entering the nucleus

Hormone Response Elements (HRE)

Steroid-receptor complex binds to these recognition/acceptor sites on DNA

Changes the configuration of DNA strands/availability of genes for transcription to mRNA

Turn on transcription, enhance rate of transcription, inhibit transcription

What can steroid hormones do?

Several

How many genes can each steroid hormone influence?

Several hours->Days->Weeks

Physiological responses to steroid hormones may take this long to be seen

Time needed for DNA->RNA (transcritpion)->mRNA to protein (translation), processing of protein, etc.

Why do steroid hormone effects take time to be seen?

Time-consuming processes required before effects of steroid hormones are seen

Cleaving of amino acid sequences, jointing of several proteins to form complexes, activation of enzymes, packaging of molecules for secretion

Dose response effects of steroids

Some actions of steroids only seen at specific concentrations

Multiple types of receptors for each steroid hormone which can influence transcription of genes

Each receptor has its own binding affinity

Steroids can bind to each other's receptors

The similarity of steroid hormone structures allows for this

Agonist

Steroid which bind to another's receptors and mimics the other's action

Antagonist

Steroid which binds to another's receptors and blocks the action

Cause an action potential

Neuromodulators do everything but this

Yes; mimics action but blocks the ability of the stronger acting hormone to have an effect

Can a steroid be a weak agonist and a an antagonist at the same time?

Hormone binds to receptor -> Triggers biochemical path -> Physiological action results

What is the general mechanism of action for hormones that bind to receptors on the cell membrane?

Receptor Structure Possesses Enzyme Activity

In this mechanism of cell membrane-binding hormones, the receptor is a transmembrane protein (or complex) that contains TYROSINE KINASE activity

Tyrosine Kinase Enzymes

This is a specific protein kinase that phosphorylates proteins at the amino acid Tyrosine

This allows one hormone to influence many functions

Activate or inhibit an enzyme, open or close a channel, activate or inhibit gene expression

Phosphorylation of a protein can do these three things:

Yes, they have different targets

Do different tyrosine kinases have different proteins as their targets for phosphorylation?

Yes. One could phosphorylate a protein at a site that activates an enzyme while another phosphorylates the same protein at a site that inhibits the enzyme

Can two hormones act in opposition through kinases?

The receptor structure itself can possess enzyme activity OR Hormones can act through G proteins/second messenger systems

Two ways that hormones can act on the cell membrane

G Proteins

These are a complex of three proteins found in the cell membrane

They are able to interact with other membrane molecules and activate or inhibit enzymes, open or close channels, etc.

Allows for the realization of the physiological effects of a hormone

Alpha, Beta, Gamma, found in the cell membrane

G proteins are complexes of these types of proteins found where?

DGP (Guanosine di phosphate)

G Alpha proteins bind this

Inactive State

In this state, G alpha, beta, and gamma proteins are associated with each other

G Gamma protein binds to GDP (Guanosine di phosphate)

Step 1 in activation of G proteins

Hormone binds to its receptor creating a hormone-receptor complex

Step 2 in activation of G proteins

Hormone-receptor complex interacts with G proteins

Step 3 in the activation of G proteins

There is a change in shape of G proteins

Step 4 in the activation of G proteins

Shape change from Step 4 causes G alpha to release GDP (which floats away)

Step 5 in the activation of G proteins

Release of GDP allows G alpha to bind to GTP

This is the activation step

Step 6 in the activation of G proteins

GTP binding to G alpha releases G beta and G gamma to move away and interact with other membrane proteins (activating or inhibiting them)

This produces the physiological effects of hormones

Both G alpha and G beta/gamma complexes interact with membrane proteins and alter their functions

Step 7 in the activation of G proteins

All of them (Alpha, Beta, Gamma)

Which G proteins (alpha, beta, and gamma) interact with membrane proteins to alter their functions?

Action of G alpha protein

Regulation of how long a hormone can act on a cell depends on this

GTPase Activity

G alpha protein possesses _______ activity.

This splits GTP into GDP + phosphate, leaving G alpha to bind with GDP

G alpha/GDP recombines with G beta/gamma and stops their actions on other molecules, halting the effects of the hormone

Returns them to step 1/inactive state

G alpha protein possesses GTPase activity.

This splits GTP into GDP + phosphate, leaving G alpha to bind with GDP

G alpha/GDP recombines with G beta/gamma and stops their actions on other molecules, halting the effects of the hormone

Returns them to step 1/inactive state

How does G alpha regulate how long a hormone can act on a cell?

Hormone action continues longer than normal

Hormone action is accentuate and prolonged

What happens if GTPase activity is blocked?

Biphasic Action

GTPase action being blocked is related to what type of action/effect of a hormone?

Cholera toxin

This is in inhibitor of GTPase activity

High levels of cyclic AMP is produced and is able to bind to the regulator protein of cyclic GMP dependent protein kinase (which generally doesn't bind to it due to low affinity)

Results in overstimulation of cyclic GMP protein kinase

Produces severe dehydration, hypotension, circulatory shock, death

Cancer

G protein abnormalities may lead to this chronic illness

Accentuated or blocked hormone actions

Mutated G proteins can have these two actions

Adenyl cyclase system

A second messenger controlled by G proteins

This hormone binds to a transmembrane receptor on the outside of a cell membrane

Hormone-receptor complex has a different shape than the actual receptor

G proteins change the shape and produce the physiological effect of the hormone

Receptor complex is shaped differently than receptor

Hormone-receptor complex interacts with G proteins to activate them, changing their shape

G proteins then activate the Adenyl Cyclase enzymes which converts ATP into Cyclic AMP

Cyclic AMP activates specific protein kinase enzymes

Protein Kinase A phosphorylates specific proteins at specific sites

Changes the proteins' shaw and functions leading to physiological action

How do G proteins interact with the Adenyl cyclase system?

The Cascade Effect

The effect of one molecule of hormone can be multiplied several times through the action of second messenger molecules

The Cascade Effect

Each molecule of hormone binds to one receptor -> One receptor can activate a few G proteins -> One G protein can activate a few molecules of adenyl cyclase -> One adenyl cyclase enzyme can produce many molecules of Cyclic AMP -> Two molecules of Cyclic AMP are needed to activate two protein kinase molecules -> One protein kinase can phosphorylate many enzyme molecules -> One active enzyme molecule can produce many molecules of product

1) GTPase activity of G alpha

2) Once a hormone/receptor complex has activated G proteins, the hormone/receptor complex will be internalized and no longer act to activate the G proteins

The hormone will be destroyed and the receptor may be destroyed or reinserted in the membrane to be used again

How is the extent of hormone action regulation?

Down regulation of hormone receptors

Loss of hormone receptors leads to decreased sensitivity (responsiveness) to the hormone

This is a rapid process occurring over a period of minutes

Especially important to prevent over stimulation of cells by excessive hormone levels

Up regulations of hormone receptors

Increased synthesis and insertion of receptors on the cell membrane

Occurs over hours or days

See increased sensitivity and response to a hormone develop over a period of time

Example is changes of responsiveness to hormones at puberty and during pregnancy

The INTRAcellular concentration of Cyclic AMP

The number of molecules of protein kinase that are activated depends on what (in the case of Cyclic AMP)?

Phosphodiesterase

This is an enzyme which destroys cyclic AMP

Adenyl Cyclase/Phosphodiesterase

ATP is converted to Cyclic AMP (active) via ______which is converted to AMP (inactive) via ______

By activating phoshodiesterase (which destroys Cyclic AMP)

How do hormones which antagonize the action of other hormones that work via Cyclic AMP do this?

Potentiate/Increase their effectiveness

Drugs that inhibit phosphodiesterase do what to hormones which act via cyclic AMP?

Caffeine, theophylline

What are some drugs which inhibit phosphodiesterase/stimulate hormones that use cyclic AMP?

Variation of the number of protein kinase molecules and the specific types of protein kinase molecules over time

Variations in this can lead to different qualitative and quantitative responses to the same hormone acting via the same second messenger molecule

Proteins that it phosphorylates

Each protein kinase has its own set of these

Ca++/Calmodulin

Phospholipids:
Diacylglycerol (DAG), Inositol Triphosphate (IP3)

Eicosanoids:
Prostaglandins and Leukotrienes

Second messenger molecules that're activated by by G proteins

Yes

Can a hormone act on different types of receptors on a cell and produce some of its effects through different things (like cyclic AMP, DAG, Ca++, etc.)?

Yes

Example would be effects produced using cyclic AMP being inhibited while those that occur through Ca++ remain unchanged

Is it possible for chemical signals to alter one set of a hormone's effects without influencing other effects of the hormone?

The Phospholipase C Second Messenger System

After a hormone binds to a receptor and activates the appropriate family of G proteins, a membrane bound enzyme is activated.

This converts a membrane phospholipid called Phospho-inol-pyruvate (PIP2) two second messenger molecules (Diacyl glycerol/DAG and Inositol triphosphate/IP3)

Phospho-inol-pyruvate

What membrane phospholipid is converted in the Phospholipase C second messenger system?

Diacyl Gylcerol (DAG)

Inositol Triphosphate (PIP2)

What two messenger molecules is phosphor-inol-pyruvate converted into in the Phospholipase C second messenger system

Dacyl Glycerol (DAG)

These are often membrane-associated

They phosphorylate ion channels and other membrane-associated proteins

Inositol Triphosphate (IP3)

This causes the release of intracellular calcium store from the ER

Diacyl Glycerol

This causes an opening of the cell membrane calcium ion channel

Enzymes and microtubules/Alteres their activities

What types of proteins does calcium interact with and what does it do?

Calcium-Calmodulin complex

This complex involving calcium can alter other enzyme activities

Act as a second messenger molecule, bringing about the phosphorylation of its own group go proteins

Lets Ca act like DAG, cyclic AMP, and cyclic GMP

Calcium-dependent protein kinases allow allow calcium to do what?

IP3

What causes the release of intracellular calcium stores from the ER?

DAG

What causes opening of the cell membrane Ca ion channel (and the release of intracellular Ca stores)

Calcium

This interacts with proteins (enzymes and microtubules) to alter their activities

Calcium

This binds to calmodulin

Ca-Calmodulin Complex

This complex can alter other enzyme activities

With cyclic GMP, the internal portion of the hormone receptor possesses the Guanyl cyclase activity

What is the major difference between cyclic GMP and cyclic AMP?

No

It's activated by the hormone binding to the receptor, like with Tyrosine Kinase

Is cyclic GMP activated by G proteins?

Guanyl Cyclase

This converts Guanosine Triphosphate to cyclic GMP

It activates cyclic GMP-dependent protein kinases wich phosphorylate specific proteins altering their shapes and activities

What does cyclic GMP do?

Cyclic GMP and AMP

These often act as breaks and accelerators to each other

Cyclic AMP speeds it up

Cyclic GMP slows it down

This cyclic speeds up heart rate, and this other one slows it down

Cyclic GMP speeds up cell division

Cyclic AMP stops division and encourages cellular functions

This cyclic stimulates cell division, and this other one stops it and stimulates mature cellular functions

They break one of the ester bonds between Guanosine and phosphate

Turn it into the inactive Guanosine Monophosphate

What do Cyclic GMP phosphodiesterases do?

Inhibits specific cyclic GMP phosphodiesterases

Allows the accumulation of cyclic GMP -> Leads to increased production of NO -> Causes increased blood flow to region served by the blood vessels

What does viagra do?

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