Hormonal regulation

Receptor Mediated Hormonal

Regulation

By: Hina

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Contents

Hormones

Mechanism of action of hormones

Physiological roles of hormones

Site of synthesis of hormones

Target sites of horomes

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Hormone

Hormones are chemical messengers secreted into blood or

extracellular fluid by one cell that affect the functioning of

other cells.

“ON”

“OFF”

Targetcell

Cellorigin

(Effects)

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Mechanism of action of hormones

The ability of a hormone to induce a response in a target cell is

usually mediated by a hormone receptor on, or in, the target

cell.

RECEPTOR

Receptors are the sensing elements in system of chemical

communication that cordinate cellular function in our body.

The binding sites on the target cells are called

hormone receptors.

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Types of Hormone Receptors

Cell surface receptors

G-Protein coupled receptor

Kinase linked receptor

Intracellular Receptors

Nuclear receptor

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Cell surface receptors


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Adenylate cyclase mediated pathway

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Hormone Action using cAMP Second Messenger

Glycogen

synthase a

Glycogen

synthase b

Protein kinase

(Inactive)Protein kinase

(Active)Phosphoprotein

phosphatase

Insulin

(+)

(+)(+)

(+)

Glycogen

Phosphorylase b

Glycogen

Phosphorylase a

Glycogen

Glucose-1-PO4

(+)

GLYCOGENOLYSIS

Phosphorylase

kinase (inactive)

Phosphorylase

kinase (active)

Phospho-

protein

phosphatase

Adenylate

cyclase

(+)

(-)

(+)

Muscles Liver

Adenylate cyclase mediated pathway

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Phospholipase mediated pathway

Receptor

DAG

IP3

Ca++

Protein kinase C

Phosphoproteins

Proteins

Physiologic responses

Ca++-Calmodulin

Calmodulin kinases

(+)

(+)GDP GTP

Phospholipase C

GTP GDP

(+)

PIP2

Hormone Action using DAG, IP3 and Ca++

as Second Messengers 10

Mechanism of Tyrosine Kinase Receptors

When hormone binds to the extracellular domain the receptors aggregate


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When the receptors aggregate, the tyrosine kinase domains phosphorylate

the C terminal tyrosine residues


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This phosphorylation produces binding sites for proteins with SH2 domains.

GRB2 is one of these proteins. GRB2, with SOS bound to it, then binds to the

receptor complex. This causes the activation of SOS.


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SOS is a guanyl nucleotide-release protein (GNRP). When this is

activated, it causes certain G proteins to release GDP and exchange it for

GTP. Ras is one of these proteins. When ras has GTP bound to it, it

becomes active.


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Activated ras then causes the activation of a cellular kinase called raf-1


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Raf-1 kinase then phosphorylates another cellular kinase called

MEK. This cause the activation of MEK


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Activated MEK then phosphorylates another protein kinase called MAPK

causing its activation. This series of phosphylating activations is called a

kinase cascade. It results in amplification of the signal


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Among the final targets of the kinase cascade are transcriptions factors (fos

and jun showed here). Phosphorylation of these proteins causes them to

become active and bind to the DNA, causing changes in gene transcription


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Hormone Metabolism

JACK/STAT Pathway

ES utilized by Growth hormone, Prolactin, EPO, cytokines…

Regulates transcription

Nucleus

Dimerization

X = SHC

GRB2

PLC

PI-3K

GAP

JAK PJAKP

P P

P P

STATs

XSH2P

P)

(

JAK PJAKP

P P

P P

JAK JAK


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Intracellular (nuclear) receptor mediated pathway

Basic Structure of nuclear receptor

Hormone-bindind

domain

DNA-binding

domain

Transcription-

activating domain

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Hormones that can cross the membrane (e.g.

steroid hormones) bind

to the receptor inside the cell, at the cytoplasm, or

they will enter the nucleus and bind nucleus and

bind to the receptor at the nucleus and initiate

transcription

Intracellular (nuclear) receptor mediated pathway

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The signal pathway by steroid hormones

Nuclear receptor mediated pathway

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The signal pathway by steroid hormones

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Insulin Pancreas Controls blood-sugar level and storage of glycogen.

Glucagon Pancreas Stimulates conversion of glycogen to glucose; raises blood sugar level.

Oxytocin Pituitary gland Stimulates contraction of the uterine muscles and secretion of milk by the mammary glands.

Vasopressin Pituitary gland Controls water excretion by the kidneys; stimulates contraction of the blood vessels.

Growth hormone Pituitary gland Stimulates growth.

Adrenocorticotrophic Pituitary gland Stimulates the adrenal cortex, which,in turn,releaseshormone (ACTH) several steroid hormones.

Prolactin Pituitary gland Stimulates milk production by the mammary glands after birth of baby.

Epinephrine Adrenal glands Stimulates rise in blood pressure, acceleration of heartbeat, decreased secretion of insulin, and

increased blood sugar.

Hormone Source Principal functions

Physiological role of Hormones

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Cortisone Adrenal glands Helps control carbohydrate metabolism, salt

and water balance, formation and storage of

glycogen.

Thyroxine & Thyroid gland Increases the metabolic rate of carbohydrates

Triiodothyronine and proteins.

Calcitonin Thyroid gland Prevents the rise of calcium and phosphate in the

body.

Parathyroid Parathyroid gland Regulates the metabolism of calcium and

phosphate in hormone in the body.

Gastrin Stomach Stimulates secretion of gastric juice.

Secretin Duodenum Stimulates secretion of pancreatic juice.

Estrogen Ovaries Stimulates development and maintenance of

female sexual characteristics.

Progesterone Ovaries Stimulates female sexual characteristics and

maintains pregnancy.

Testosterone Testes Stimulates development and maintenance of male

sexual characteristics.

Hormone Source Principal functions

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Types of Hormones

Catecholamines and Thyroid Hormones

Small and derived from amino acids (epinephrine,

thryoxine.)

Steroid Hormones and Vitamin D

Relatively small and derived from cholesterol

Prostaglandin's

Relatively small and derived from fatty acids

Proteins or Polypeptides

Relatively large and derived from translation of hormone

specific mRNA (growth hormone, insulin)

Site of synthesis of various hormones

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Thyroid Hormones

Synthesized solely in the thyroid gland ( T4; 3’,5’,3,5-

L-tetra-iodothyronine).

Majority of the active form, T3 (3’,3,5-L-tri-

iodothyronine), is produced in the peripheral tissues

through deiodination of T4.

Thyroid gland cells concentrates iodine for thyroid

hormone synthesis.

Iodine is attached to tyrosine residues on a protein,

termed thyroglobulin. Tyrosine residues are then

coupled together to yield thyronines.

Proteolytic digestion of thyroglobulin then yields T4

and T3 in a 10:1 ratio.

Helps in the metabolism of sugars.

The half life of T4 is 7 days and that of T3 is 1 day.

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Steroid Hormones

Produced in the adrenals, ovaries, testes, and placenta.

Derived from cholesterol.

Enzymes in the various glands control the final product.

For example, cytochrome P450c11 which is located in

the adrencortical cells, is involved in coritsol

production. This enzyme is lacking in the gonads, that

do not produce cortisol or aldosterone.

Gonads, however, can produce dihydroxytestosterone,

estradiol, or progesterone depending upon the enzymes

present in the gonadal tissue.

Over 50 different steroid metabolites have been

described.

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Catecholamines

Are synthesized in nervous tissues from which the adrenal

medulla is derived.

Adrenal medulla is the major source for circulating

epinephrine.

Synthesized from tyrosine which is converted to

dihydroxyphenylalanine (DOPA) by tyrosine hydroxylases.

Subsequent conversions to dopamine and then to nor

epinephrine which is released by most catecholamine-

producing cells of the body.

In the adrenal medulla and a few other tissue, nor epinephrine

is converted to epinephrine.

The half life is 1-2 minutes.

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Prostaglandins and Leukotrienes

They can be produced by most cells depending upon lipid

and enzyme content of the cells.

Arachidonic acid, which is derived from lipid metabolism,

is the precursor compound.

Depending upon the lipoxygenase present in the cell,

either, HETE, prostaglandin (G2) or leukotrienes

Cyclooxygenase (involved in PGG2 synthesis) is widely

distributed throughout the body and is inhibited by aspirin,

indomethacin, and other nonsteroidal and anti-

inflammatory agents.

The half-life is a few seconds.

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Target Sites of hormones

Target cells: Cells that respond to a specific hormone

Can be found anywhere in the body

All target cells have receptors that detect

specific hormones

Ex:

Thyroid hurmone act on almost all cells of

the body to increase rate of metabolism

Hormones specifically affect or alter the

activities of the responsive tissue (target

tissue).

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1. Endocrine

Chemicals act on distant cells via the bloodstream Ex: thyroxine, sex hormones

2. Paracrine

Chemicals act on the surrounding cells or neighboring tissues

without entering the blood

Ex: GIT hormones

3. Autocrine

Chemicals act on the cell that produce it

Ex : nitric oxide

4. Neuroendocrine

Synthesize & release into blood stream by nerves

signals between neurons

Ex: neurotransmitters ( Ach, dopamine)

Actions of hormones

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Endocrine Blood vessel

Distant target cellsHormone secretion

into blood by

endocrine glandParacrine

Secretory cell Adjacent target cell

Autocrine

Target sites on same cell

Receptor

Hormone or

other extra

cellular

signal35

Second target mechanism

By receptors and target cells

The receptor and target cell action depends on

two terms broadly

Agonist

Antagonist

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Agonists

Agonists are molecules that bind the receptor and induce

all the post-receptor events that lead to a biologic effect

Natural hormones are themselves agonists.

For a given receptor, different agonists can have

different potencies

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Antagonist

Antagonists are molecules that bind the receptor and

block binding of the agonist, but fail to trigger intracellular

signalling events.

They don't themselves perform useful work, but block

the activities of those that do have the capacity to

contribute.

Hormone antagonists are widely used as drugs.

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Antagonist to Use1. Growth Hormone Acromegaly, Diabetes

2. Progesterone Contraceptive, abortion

3. Glucocorticoid Spontaneous Cushing’s Syndrome

4. Mineralo-corticoid Primary and secondary

mineralocorticoid excess

5. Androgen Prostate cancer

6. Estrogen Breast cancer

7. GnRH Prostate cancer

8. Adrenrgic Hypertension, hyperthyroidism

9. Prostaglandin Acute and chronic inflammatory

disease

Examples of hormone antagonist used in therapy

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When you do not succeed in taking giant steps on the road to your goal, be satisfied with little steps,

and wait patiently till the time that you are able to run, or better still, to fly.

Be satisfied to be a little bee in the hive who will soon become a big bee capable of making

honey…

Thank you …

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Hormonal regulation

Education

Transcript of Hormonal regulation