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MECHANISM OF HORMONE ACTION

HORMONE

a chemical messengers

secreted into blood by endocrine cells

transported to distant targets that affect function of other cells. Most hormones circulate in blood, coming into contact with essentially all cells

given hormone usually affects only a limited number of cells, which are called target cells

A target cell responds to a hormone because it bears receptors for the hormone

All hormones act through binding to specific receptors, whether the receptors are located inside the target cell or on the cell surface

The presence of specific receptors on the specific cell types determines how hormones although secreted into the bloodstream affect only certain tissue (receptor specificity)

PREPROHORMONE PROHORMONE PREHORMONE

prohormone derived from larger precursor molecule

not biologically active

cleaved to form prohormone in ER

Inactive until changed into hormone by target cells

Transferred to GA for packaging into secretory vesicles

Molecules secreted by endocrine glands that are inactive until changed into hormone by target cells. Eg : T4 converted to T3.

SIGNAL TRANSDUCTION

process in which cells convert and amplify an extra cellular signal into an intracellular signal.

When a ligand binds to a receptor, it can activate a second protein in the membrane and produce actions.

CELL SIGNALING The mechanism by which cells communicate with one another.

ENDOCRINE ACTION PARACRINE ACTION AUTOCRINE ACTION

hormone is distributed in blood

and binds to distant target

cells.

hormone acts locally by diffusing from its source to target cells in the neighborhood

hormone acts on the same cell

that produced it

SOMATOSTATIN GROWTH FACTORS

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CLASSIFICATION OF HORMONES

1. ACCORDING TO CHEMICAL NATURE STEROID HORMONES NON STEROID HORMONES

AMINO ACID DERIVED PEPTIDE

These hormones are derived from

1. Cholesterol-regulate metabolism

2. Salt/water balance 3. Inflammation 4. Sexual function

Regulate: 1. smooth muscle 2. blood pressure 3. cardiac rate 4. lipolysis 5. glycogenolysis.

1. Regulate many process in all tissues

2. Release of other hormones

Glucorcorticoids

Mineralocorticoids

Sex hormones (adrogens & estrogens)

Cathecholamines

Thyroxin

Melatonin

Large PP

GH

Insulin

glucagon

Small PP

ADH

Glycoproteion (FSH, LH)

2. ACCORDING TO MECHANISM OF ACTION HORMONES THAT BIND TO

INTRACELLULAR RECEPTORS HORMONES THAT BIND TO MEMBRANE RECEPTORS

Lipophylic/ Hydrophobic Hydrophilic

Need transport protein to their target tissue

Don’t need transport protein to reach their target tissues

Plasma half-life : long (hrs-days) Plasma half-life : short (mins)

Onset : slow Onset : fast

Receptors : cytosol or nucleus Receptors : membrane-bound

Form hormone-receptor complex

Affect level of transcription

Binding of hormone to receptor produces 2nd messenger:

(cAMP)

(cGMP)

Protein kinase cascade

Calcium or phosphatidyl inositol or both

Steroid hormones

Thyroid hormones

Calcitriol

Retinoids

FSH

LH

TSH

HCG

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STRUCTURE OF INTRACELLULAR RECEPTORS (STEROID HORMONES) - Lipophilic

STRUCTURE OF CELL SURFACE RECEPTORS (NON STEROID HORMONES) -Hydrophilic

Located in cytoplasm and in the nucleus

Function within the cell to activate

genetic transcription

Messenger RNA directs synthesis of

specific enzyme proteins that change

metabolism

Each nuclear hormone receptor has 2

main regions:

1. A ligand-binding domain

2. DNA- binding domain

Cell surface receptors are integral membrane proteins

with 3 basic domains:

1. Extracellular domains:

Exposed to the outside of the cell interact with

and bind to the hormone

Ligand-binding domain

2. Transmembrane domains:

Serve to anchor the receptor in the membrane

3. Cytoplasmic or intracellular domains:

Tails or loops of the receptor that are within

the cytoplasm react to hormone binding by

interacting in some way with other molecules,

leading to generation of second messengers

Cytoplasmic residues of the receptor are thus

the effector region of the molecule

LOCATION OF HORMONE RESPONSE ELEMETS (HREs)

Located adjacent to gene that will transcibed

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DIMERIZATION process of 2 units coming together at the 2 half sites

stimulates transcription of particular genes.

Mechanism of genomic transcription via nuclear steroid/ thyroid hormone receptors

HORMONES THAT USE SECOND MESSENGERS

Hormones cannot pass through plasma membrane use second messengers

Catecholamine, poplypeptide, and glycoprotein hormones binds to receptor proteins on the

target plasma membrane

Actions are mediated by second messengers (signal-transduction mechanisms)

Extracellular hormones are transduced into intracellular second messengers

SECOND MESSENGER

EXAMPLES OF HORMONES WHICH UTILIZE THIS SYSTEM

CYCLIC AMP PROTEIN KINASE ACTIVITY

CA & PHOSPOHOINOSITIDES

CYCLIC GMP

1. Epinephrine 2.Norepinephrine 3. Glucagon 4. Luteinizing H

5. Follicle SH 6. Thyroid SH 7. Calcitonin 8. PTH 9. Antidiuretic H

1. Insulin 2. Growth Hormone 3. Prolactin 4. Oxytocin 5. Erythropoietin 6. Several GF

1. Epinephrine 2. Norepinephrine 3. Angiotensin II 4. Antidiuretic H 5. Gonadotropin RH 6. Thyroid RH

1. Atrial Natriuretic H 2. Nitric Oxide

1. Lipophilic steroid and thyroid hormones are attached to

plasma carrier proteins

Hormones dissociate from carrier proteins to pass through

lipid component of the target plasma membrane

Receptors for the lipophilic hormones are known as nuclear

hormone receptors

2. Cytoplasmic receptor binds to

steroid hormone

Translocate to nucleus

DNA-binding domain binds to

specific HRE of the DNA

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MECHANISM OF HORMONAL ACTION HORMONES WHICH BIND TO CELL MEMBRANE RECEPTORS

(MOA of Second Messenger System)

These hormones bind to their specific receptors on the cell membrane.

This binding causes the formation of the SECOND MESSENGER.

I. CYCLIC ADENOSINE MONOPHOSPHATE (CAMP) 1. Binding of hormones w receptor allows coupling of receptor to G protein 2. Active G protein stimulates adenylyl cyclase- cAMP system. 3. Stimulated adenylyl cyclase catalyzes the conversion of ATP into cAMP inside cell 4. cAMP then activates cAMP-dependant protein kinase. 5. Active PKa phosphorylates specific proteins in the cell, triggering biochemical reactions that lead to cell’s response to the hormone. Binding Actions of G proteins

G Protein-regulated enzymes and second messenger

Hormone stimulates receptor

→ which activates G Protein (GTP

binding protein)

→ which activates AC

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2. CYCLIC GUANOSINE MONOPHOSPHATE (cGMP)

Guanylyl cyclase maybe in:

3. CALCIUM & PHOSPHOLIPIDS

1. Binding of Epi to a-adrenergic receptor in plasma

membrane activates a G-protein intermediate,

phospholipase C

2. Phospholipase C splits phospholipid into IP3 and DAG

3. Both derivatives serve as second messengers

4. IP3 diffuses through cytoplasm to ER

5. Binding of IP3 to receptor protein in ER causes Ca2+

channels to open

6. Ca2+ diffuses into the cytoplasm & binds to calmodulin

7. Calmodulin activates specific protein kinase enzymes

8. Alters the metabolism of the cell, producing the hormone’s effects

PHOSPHATIDYL INOSITOL

MEMBRANE BOUND FORM

CYTOSOLIC SOLUBLE FORM

Atrial Natriuretic Peptide

NO

Nitroglycerine

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CELL SURFACE RECEPTORS ION CHANNEL LINKED RECEPTORS

The receptor may be part of the ion channel.

1. Changing the electrical properties of a cell through ligand gated channels. 2. Changing cytosolic calcium levels through ligand gated channels

The receptor activation may gate the ion channel

- Action of G protein on a slow ligand gated ion channel

ENZYME LINKED RECEPTORS (protein kinase cascade) ↑

Tyrosine kinases:

Group of enzymes which phosphorylate their substrates on tyrosine residues.

May be:

1. Insulin receptor consists of 2 units that dimerize when they bind

with insulin

2. Insulin binds to ligand-binding site on plasma membrane, activating

enzymatic site in the cytoplasm

3. Autophosphorylation occurs, increasing tyrosine kinase activity

4. Activates signaling molecules

5. Stimulate glycogen, fat and protein

synthesis

6. Stimulate insertion of GLUT-4 carrier

proteins

Intrinsic part of the receptor

Intracellular associated with the receptor

(but not intrinsic part of it)

Insulin receptors Receptors of GH and prolactin