Mechanism of Hormone Action

Mechanism of Hormone Action Each hormone exerts a characteristic

effects on the target organ by acting on the cells of the organ But same chemical category of hormone

have similar mechanisms of action Involves

a. Location of cellular receptor proteinsb. Events occurring in the target cells after

the hormone has combined w/ its receptor protein

Mechanism of Hormone Action Hormones are delivered by blood to

every cell in the body But! Only target cells are able to respond

to these hormones. Target cells must have specific receptor

proteins that is SPECIFIC Hormones bind with a high affinity and

low capacity

Location of Hormone’s Receptor Protein Depends on the chemical nature of hormone

Lipid-soluble hormone receptor are located within the target cells Because they can pass through cell membrane

and enter target cell Water-soluble hormone receptor are located

outside the target cells Because they can’t pass through cell membrane Therefore they need the activation of 2nd

messengers within the cell for hormone action

Lipid-soluble Hormone ActionHormones includes thyroid and steroid hormones + nitric acid

Attached to plasma carrier proteins then dissociate to pass thru lipid component of plasma membrane to enter cell where the receptor proteins are located

Lipid-soluble Hormone Action Receptor are called “nuclear hormone

receptors” Because they func. w/in the nucleus to

activate genetic transcription (production of mRNA)

Thus func. as transcription factors Has two regions or domains

a. ligand-binding domain/hormone-binding domain

b. DNA-binding domain

Nuclear Hormone Receptors With two families:

a. Steroid family b. Thyroid Hormone family – includes

receptors for active form of Vit. D and for retinoic acid that play important roles in the regulation of cell function and organ physiology

Receptors for unknown hormone ligands are called “orphan receptors”

Mechanism of Steroid Hormone Action1. Hormone-receptor binding(in

cytoplasm)2. Translocation to nucleus3. DNA-binding domain binds to specific

hormone-response element of DNA• Hormone response element of DNA

have two half-sites, each 6 nucleotide bases long, separated by 3-nucleotide spacer segment.

Mechanism of Steroid Hormone Action One steroid receptor binds to one half-

site and another to the other half-site Thus called “dimerization” “Monodimer” due to same receptor unit

binds to the DNA hormone-response element

Ligand-binding domain

DNA-binding domain

Steroid hormone

Hormone-response element

Half-sites

DNA

Dimerization of receptors

Genetic transcription RNA

Mechanism of Thyroid Hormone Action Major hormone secreted is thyroxine or

tetraiodothyrinine(T4) Small amount of triiodothyronine (T3)

Travels through blood and attached to carrier proteins primarily “thyroxine-binding globulin” or TBG which has higher affinity to T4 than T3

Mechanism of Thyroid Hormone Action Approximately 99.96% of thyroxine in the

blood is attached to carrier proteins in the plasma • The rest are free

Only thyroxine and T3 can enter target cells Protein bound thyroxine serves as reservoir

of the hormone in the blood Once free thyroxine enter cytoplasm, it is

enzymatically converted to T3• T3 is the one active in cytoplasm

Mechanism of Thyroid Hormone Action Inactive receptor proteins for T3 are

located in the nucleus Incapable of binding to DNA and

stimulate transcription unless bind with T3

T3 enters cell from plasma or may be produced in the cell by converting T4

Needs a binding protein to enter nucleus

Mechanism of Thyroid Hormone Action Difference to steriod:

Binds with non-specific binding protein in the cytoplasm

nuclear receptor is heterodimer(diff. receptor proteins attached to the half-sites)

Water-soluble Hormone Action Includes catecholamines (epi and

norepinephrine), polypeptides and glycoproteins

Cannot pass through lipid barrier of target cell

Some may enter through “pinocytosis” but mostly acts on the outer surface of the target cell and therefore can be mediated by other molecules

Uses 2nd messenger to exert their effects

Second-messenger SystemsA. Adenylate Cyclase-Cyclic AMP (cAMP)

Second Messenger SystemB. Phospholipase C-Ca2+ Second-

Messenger SystemC. Tyrosine Kinase Second-Messenger

System

Adenylate Cyclase-Cyclic AMP(cAMP) Second Messenger System For activation of adenylate cyclase First known and understood “second

messenger” Responsible for b-adrenergic effects of

epi and norepinephrine

Cyclic Adenosine Monophosphate Hormone(water-soluble) binds to

receptor protein results to dissociation of subunit from the G-protein

G-protein subunits moves thru membrane to bind and activates adenylate cyclase as catalyst ATP cAMP + Ppi

Intracellular concentration of this increases

Cyclic Adenosine Monophosphate Activates protein kinase

Inactivated form: Catalytic subunit and inhibitory subunit

Becomes active once cAMP binds to inhibitory and dissociate from catalytic subunit

in summary, the hormone causes an increase in protein kinase enzyme activity within its target cells

Cyclic Adenosine Monophosphate Active protein kinase catalyzes

phosphorylation of diff. proteins in the cell causing some enzymes to be activated and others to be inactivated

cAMP must be rapidly inactivated by phosphosdiesterase to function effectively

Phospholipase C-Ca2+ Second Messenger System Ca pumps in the plasma membrane and

endoplasmic reticulum keeps Ca concentration very low in the cytoplasm

The steep concentration gradient for Ca that results allows various stimuli to evoke a rapid diffusion of Ca into the cytoplasm that serves as a signal in diff. control systems

The entry of the Ca thru voltage-regulated Ca channels in the plasma membrane serves as a signal for the release of neurotransmitters

Phospholipase C-Ca2+ Second Messenger System When epinephrine stimulates target

organ, it must first bind to andrenergic receptor proteins in the membrane

2 types of adrenergic receptors:a. Alpha b. Beta

Alpha adrenergic receptors by epinephrine activates the target cell via the Ca second-messenger system

Phospholipase C-Ca2+ Second Messenger System G-protein intermediate enables binding

of epinephrine to alpha-adrenergic receptor and the binding activates phospholipase C• Substrate is split by an active enzyme

into inositol triphosphate (IP3) and diacylglycerol (DAG) that both acts as second messengers but IP3 is better understood

Phospholipase C-Ca2+ Second Messenger System IP3 leaves the plasma membrane and

diffuses thru the cytoplasm to the endoplasmic reticulum• Membrane of ER has receptor for IP3 so

the message of hormone is carried by IP3 from cytoplasm to ER The binding of IP3 to receptor causes

specific Ca channels to open.

Phospholipase C-Ca2+ Second Messenger System Results to rapid and transient rise of

cytoplasmic Ca concentration Ca that enters the cytoplasm binds to a

protein called “calmodulin” Activated calmodulin then activates

other specific protein kinase enzymes that modify actions of other enzymes in the cell

Tyrosine Kinase Second-Messenger System Insulin promotes glucose and amino

acid transport and stimulates glycogen, fat and protein synthesis

Primary target organs are liver, skeletal muscles and adipose tissue

Insulin’s mechanism of action is same with growth factors’

Insulin Mechanism of Action “Tyrosine kinase” is the enzyme that serves as

receptor protein for insulin and GF Specifically adds phosphate groups to amino acid

tyrosine with in the protein With two units(dimer) when binds to insulin forming

active tyrosine kinase enzyme Each unit have ligand-binding site and an

enzymatic site Ligand binding site-outside site that binds with insulin Enzymatic site-part that spans the plasma membrane

Insulin Mechanism of Action Enzymatic site activates only after

binding of insulin to ligand-binding site and causes dimerization of the receptor

One unit then phosphorylates the other

- “autophosphorylation” Signaling molecules are proteins

phosphorylated by the activated tyrosine kinase receptor Activates second messenger systems

Insulin Mechanism of Action The complex reactions enables the

insulin to regulate the metabolism of its target cells. Example:• binding of insulin to its receptor

indirectly causes the activation of “glycogen synthetase”

Enzyme in liver and skeletal muscles that catalyzes the production of glycogen