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Omran Saeed

Mamoon Mohammad alqtamin

Ebaa ALzayadneh

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Revision:

*classification the signals according to the location of their receptors: (signals have

receptors either)

1 – transmembrane receptors ( integral receptors , receptors are embedded in the

plasma membrane ): a) ion channel linked receptors b) G- protein

coupled receptors c) enzyme coupled receptors

2 – Intracellular receptors: a) cytoplasmic receptors b) nuclear receptors

*classification according to the distance that should be travelled by the signal to reach

the target cells: a) autocrines (secreting hormone from one cell to affect the same cell)

b) Paracrines (the signals act on a neighboring cells that have receptors for these

signals, these signals are transported in the interstitial fluid)

Note: both paracrine and autocrine are considered local modulators

c) Endocrine hormones (are transporting via blood to reach the target cells, and

secreting by glands or certain types of cells)

d) Neural or synaptic signals: 1) neural: releasing neurotransmitters from one neuron to

adjacent neuron at the synapse 2) neuroendocrine hormones: are secreted by neurons

into the circulating blood and influence the function of target cells at another location in

the body

Types of signaling ligands (depending on the locations of the

receptors).

1- Ligands that bind to transmembrane receptors ي التعبر الغشاءالعام كل المبدأ ((المواد الت .

Usually these signals are due to incapability of the signal to easily cross the

plasma membrane (usually when the signals are not lipophilic and can’t cross the

plasma membrane there must be receptor on the cell surface to transduce

signal). In general these receptors for (proteins, peptides, catecholamine

hormones)

It could be for:

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♦ Neurotransmitter (NT), i.e. epinephrine, norepinephrine, and histamine

• Hydrophilic (charged, polar). That’s why they require receptors on the cell surface.

♦ Peptide hormones (P), i.e. insulin.

• can't cross membrane.

♦ Growth factors (GF), i.e. NGF, EGF, PDGF

♦ Lipophilic signaling molecules, i.e. prostaglandins.

Note : this hormone ( prostaglandins) is an exception , because of high receiving of

this hormone from high number of cells makes the scientist suggest that this

hormone has a transmembrane receptor ( prostaglandins transporter )

2- Ligands that bind to intracellular receptors.

Lipid soluble hormones that can easily diffuse across the plasma membrane and

interact with receptors in the cytosol or nucleus. I.e. Steroids, thyroxine, retinoic

acid, or gases such as nitric oxide (NO). Those can affect intracellular receptors.

NOTE: the receptors for the thyroid hormones are found in the nucleus

Note: the thyroid hormones have to pass the cell membrane in order to reach the

receptors in the nucleus, this process occurs by carrier mediate transport which is ATP

dependant

Local vs. circulating hormones

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Chemical classes of hormones:

1- Lipid soluble hormones

(like steroids) which can easily cross the plasma membrane (because they are

lipophilic), and in the plasma (blood) they must be carried by proteins (These proteins

carry them and protect them from being easily filtered in the kidney, So their clearance

rate is very high if they are unbound because they are being cleared all the time and

they easily diffuse if they are free but if they are bound with proteins and proteins often

don’t cross the kidney’s membranes…..(filtration membrane) that protects them

increases their life. ☺

•In the plasma membrane they don’t require receptors in the cell surface (It

doesn’t mean that they don’t bind to receptors) their receptors inside the cell

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Examples of lipid soluble hormones:

- Steroids : Lipids derived from cholesterol

Testosterone.

Progesterone.

Estradiol.

Cortisol (from adrenal cortex).

- Thyroid ( amine but lipid soluble)

- Nitric oxide (NO) (important hormone because It binds with receptors, changes

functions, and makes signaling, so it is actually a vasodilator).

2- Water soluble hormones:

They simply free in the plasma (blood) and they don’t require proteins to be bound

to at the same time they require receptors in the plasma membrane to induce signaling

(because they can’t cross the plasma membrane). ☺

Examples of water soluble hormones:

- Amines: Hormones derived from tyrosine and tryptophan like epinephrine and

norepinephrine.

.is derived from tyrosine but it is lipid soluble Thyroxine (thyroid) Remember:

- Polypeptides: Chains of < 100 amino acids in length like antidiuretic hormone

(ADH) which is stored in posterior pituitary gland and its function is to control

blood pressure.

- Protein hormones: Polypeptide chains with > 100 amino acids like growth

hormone.

• Most anterior and posterior pituitary gland hormones are protein

hormones.

- Eicosanoid (prostaglandins): derived from arachidonic acid (20 carbon 4 cis

double bonds) like proinflammatory mediator ……….They are local hormones.

( either paracine or autocrine ) they are synthesized in the walls of blood vessels

and have a function in the case of inflammatory

Sex hormones

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- Glycoproteins (proteins attached to sugar): Long polypeptides (>100) bound to 1

or more carbohydrate (CHO) groups like FSH and LH, TSH and HCG (human

chorionic gonadotropin).

Follicle-Stimulating Hormone

(FSH)

•Produced by anterior pituitary

gland.

•Stimulate the gonads Luteinizing hormone (LH)

Thyroid-stimulating hormone Stimulates thyroid gland to

secrete thyroxine.

Human Chorionic gonadotropin Consist in pregnant woman.

Note: 1) the alpha subunits are identical while the beta subunits are vary

(Proteins have α and β subunits (α is common and β is specific) and tertiary structure)

Hormones can also be divided into:

Polar:

0 soluble.2H

Nonpolar (lipophilic):

soluble).0 insoluble (lipid 2H

Prehormones, Prohormones, and Preprohormones

When hormones are synthesized in the secreting cells they may be synthesized into

forms precede the final form (active form), so synthesis of hormones passes through

several stages which are Preprohormones and Prohormones

Preprohormones Prohormones active hormone

1) Preprohormone synthesis occurs in the ER and is directed by a specific mRNA

2) Signal peptides are cleaved from the preprohormone, producing a prohormone,

which is transported to the Golgi apparatus

3) Additional peptide sequence are cleaved in the Golgi apparatus to form the

hormone, which is packaged in secretory granules for later release

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•Prehormone:

○ Molecules secreted by endocrine glands that are inactive until changed into

hormones by target cells.

which is 3 is a prehormone or precursor because it’s inactive or less active than T4 ○ T

the active form of the hormone>

iodothyronin). -(tri3 hyronin) converted to Tiodot-(tetra4 ○ T

Some stages of the synthesis of hormones if it’s peptide or protein first of all gene

modification of the manufactured translation mRNA (transcription) expression

proteins or peptides either in Golgi apparatus or endoplasmic reticulum by adding

specific groups like sugar then packaging and secretion. After that there will be a

Then a signal comes like calcium specific signal which induce exocytosis of the hormone.

which will mediate in exocytosis or diffusion of vesicles in order to secrete its secretion.

☺ These stages and sequences differ from one hormone to another

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Peptide & Protein Hormones

Gland/Tissue Hormones

Hypothalamus TRH, GnRH, CRH, GHRH,

Somatostatin.

Anterior pituitary ACTH, TSH, FSH, LH, PRL, GH

Posterior pituitary Oxytocin, ADH

Thyroid Calcitonin

Pancreas Insulin, Glucagon, Somatostatin

Liver Somatomedin C (IGF-1)

Parathyroid PTH

Placenta HCG, HCS or HPL Kidney Renin

Heart ANP

G.I. tract Gastrin, CCK, Secretin, GIP,

Somatostatin Adipocyte Leptin

Adrenal medulla Norepinephrine, epinephrine

Focus on peptides and proteins hormones and keep in mind that they need cell

surface receptors.

For example Renin (secreted from the kidney) is considered as enzyme responsible for

synthesis of (Angiotensin II) which is a peptide hormone. Renin itself can be considered as a hormone because it has receptors, so Renin works as enzyme and works as hormone (binds to receptors and make signals). The rest are normal hormones.

Question: In the thyroid gland. Why Thyroxine hormone isn’t written?

Answer: Because Thyroxine considered as amines which are lipophilic, also it enters the cells via carrier mediate transport.

Epinephrine and Norepinephrine also need receptors.

………………..

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Amine Hormones

Gland/Tissue Hormones

Hypothalamus Dopamine Thyroid T3, T4

Adrenal medulla Epinephrine and Norepinephrine (NE, EPI)

Dopamine hormone works mainly on central nervous system and it’s considered as neurotransmitter derived from the amino acid (Tyrosine). Outside the central nervous system it acts as a local chemical messenger (different functions on different organs)

Tyrosine will be converted into these different hormones in the presence of certain enzymes.

Question: What determine the fate of this amino acid (Tyrosine)?

Answer: The package of the enzymes in the cell.

Derived from

Tyrosine

Norepinephrine

Epinephrine

Dopamine

T4, T3

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Also thyroid hormone has pathway to produce it consist in thyroid gland’s cells.

Cortisol responses to stress and low blood glucose concentration

Aldosterone increase blood pressure. Its target is on kidney

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Androgens one of the sex hormones

Calcitriol is the active form of vitamin D

○ Let’s talk about some terms about receptors and activity of a hormone

Hormone activity:

• Hormones affect only specific target tissues with specific receptors (either the hormone is extracellular or intracellular).

• Receptors are dynamic and constantly synthesized and broken down to control the response (they aren’t found in a certain number all the time).

• Down-regulation- decrease in receptor number or response and we decrease the sensitivity of the hormone. We make a process called desensitization for the cell. This often happens as a result of prolonged stimulus then negative feedback takes place in the receptor to terminate the signal. The more the stimulus is Intermitted the less desensitization occurs. The desensitization occurs either by internalization (the receptors inter vesicles in the membrane so they can’t bind to the ligand) or the synthesis of the receptors stops. For example this happens in diabetes type 2 as a result of prolonged stimulation of insulin secretion in the blood because there is always food and glucose in it. Then the desensitization takes place for the receptors of Insulin. With the passage of time Insulin will be useless as if it’s not exist. Then the rate of glucose in blood increases. (I know you don’t understand anything)

Again you have to keep these two points in your mind:

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a) The number of receptors in the target cells usually doesn’t remain constant from day to day even from minute to minute

b) Receptors can be inactivated or destroyed ….. Reactivated or manufactured

* Down regulation occurs in different ways: 1) inactivation of some receptors

2) Inactivation of some intracellular signaling molecules

3) The receptors are trapped inside the cell away from hormones

4) Destruction of the receptors by lysosomes after they are internalized

5) Decreasing the production of the receptors

* In each case, receptor down regulation decreases the target tissue responsiveness to hormone

Sometimes desensitization is a good thing.

• Up-regulation- increase in receptor number or activity (It’s called also priming for the hormone which means that we prepare the cell to be sensitive for the hormone when we increase the synthesis of the receptors in a specific place in the cell in this way we increase the chances of binding between the ligand and the receptors. As a result we increase the activity of the hormone).

Again: 1) hormone induces production of the receptors in the target tissue to be more than normal situation

2) It leads to increase the concentration of intracellular signaling molecules

3) The target cells become more sensitive for the stimulating effects of the hormone

♣ Remember: The activity of a hormone depends on the receptors and the density of them.

(Hormone) in blood reflects the rate of secretion.

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Half-life:

Time required for the blood [hormone] to be reduced to ½ reference level.

Minutes to days.

Every hormone after its secreted has a different life span than other hormones depends on the metabolism, clearance rate and the chemical composition of the hormone.

Affinity of receptors to ligands, Kd

◘ Represented by a number called dissociation constant (Kd) which express how strong is the bond between the ligand and the receptor.

◘ Keep in mind that more than one ligand can bind to one receptor (there is no one ligand for a receptor), but not all of them have the same affinity to the receptor. Some of them have high affinity less concentration of ligands is required for a good response. For instant: epinephrine has high affinity on beta receptors than norepinephrine so the same amount of two substances are different in influence (the major influence is in the epinephrine)

◘ the lower affinity of a hormone the higher concentration of the ligands needed for a good response.

Normal tissue responses are produced only when (hormones) are presented within physiological range.

Varying (hormones) within normal, physiological range can affect the responsiveness of target cells and induce different actions. You will see in physiology that sometimes the hormone can do two opposite effects depending on its concentration.

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Mechanisms of Hormone Action

Hormones of same chemical class have similar mechanisms of action.

Similarities include:

♣Location of cellular receptor proteins depends on the chemical nature of the hormone.

♣Events that occur in the target cells.

To respond to a hormone:

Target cell must have specific receptors for that hormone (specificity).

♣Hormones exhibit:

• Affinity (bind to receptors with high bond strength). • Saturation (low capacity of receptors).

• Response depends on both hormone and target cell (if there’s a receptor on different target cell the response may be different although with the same ligand).

• Lipid-soluble hormones bind to receptors inside target cells. • Water-soluble hormones bind to receptors on the plasma membrane

• Activates second messenger system • Amplification of original small signal

• Responsiveness of target cell depends on • Hormone’s concentration • Abundance of target cell receptors.

Receptor:

Receptors are specific membrane proteins, which are able to recognize and bind to corresponding ligand molecules, become activated, and transduce signal to next signaling molecules.

• Specificity: "specificity" of a ligand for a receptor is a description of how favorable the binding of the ligand for the receptor is compared with its possible binding to other types of receptors that may also be present. For example: Ach can bind on a nicotinic and muscarinic receptors but it is impossible to bind on the adrenergic receptors.

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Explanation: Some ligands may bind to more than one receptor. Binding isn’t specific for one type of receptors. In the other side some ligands bind to only one type of receptors, so their binding is more specific every ligand has specific binding more with certain type of receptor. For example the angiotensin peptides (There’s angiotensin II and angiotensin (1-7)). There’s receptors for angiotensin peptides but the specific binding for angiotensin II is more with AT1 despite that angiotensin (1-7) can bind to AT1 …………….

• Affinity: "Affinity" simply refers to how strong the binding is. "High affinity" refers to very strong binding. The association or dissociation constant is often referred to as the "affinity” or “binding” constant.

• Ligand: A small molecule that binds specifically to a larger one; for example, a hormone is the ligand for its specific protein receptor.

• Membrane receptors: Membrane Glycoprotein. • Intracellular receptors: Cytosol or nuclei /DNA binding protein.

Membrane receptors:

1- Ligand-gate ion channels type (ionotropic receptors)

(Cyclic receptor)

Ligand→receptor→ion channel open or close

For example Acetylcholine or neurotransmitter…. the channel is ion channel so it binds to the neurotransmitter then the channel opens or closes they are membrane receptors but at the same time they are channels then action potential occurs.

Some extra information: 1) steroid hormones are derivatives of cholesterol

2) Amine hormones are derivatives from tyrosine

3) Peptides and protein hormones are similar to any protein in synthesizing

ERGolgi

apparatusexocytosis

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*REGULATION OF HORMONE SECRETION

1) negative feedback : is the most commonly applied principle for regulating hormone secretion , is self – limiting , a hormone has biologic actions that directly or indirectly inhibit further secretion of the hormone

Example: increasing in blood glucose ………. Insulin is secreted by pancreas ……… increasing uptake glucose into the cells ……. Decreasing blood glucose concentration ……. Decreases further secretion of insulin

2) Positive feedback: is rare, is explosive and self – reinforcing, a hormone has biologic actions that, directly or indirectly, cause more secretion of the hormone

Example: estrogen increases producing the LH ……. Then LH increases producing estrogen before ovulation

“Imagination is more important than knowledge” Albert Einstein

https://www.goodreads.com/author/show/9810.Albert_Einstein