Hormones and Receptors

Question 1

There are many forms of chemical communication between cells

Answer 1

a. Neurotransmitters–> chemical transmission in the nervous system.
i. neurotransmitters are secreted at specialized junctions called synapses.

b. Paracrine Effectors–> chemical substances secreted by cells may act on neighboring cells without these specialized structures
c. Alternately, if a chemical acts on the same cell that secretes it, it is an autocrine effector.

d. A hormone is a chemical that is produced by certain cells, released into the blood stream in minute amounts and has its physiological effects on target cells at a distance.
i. An endocrine gland consists of a group of cells that produce these hormones.

Question 2

Hormones

Answer 2

a. A hormone is a chemical that is produced by certain cells, released into the blood stream in minute amounts and has its physiological effects on target cells at a distance.
b. An endocrine gland consists of a group of cells that produce these hormones.

Question 3

Paracrine and Autocrine effectors

Answer 3

Other chemical substances secreted by cells may act on neighboring cells without these specialized structures and are known as paracrine effectors. Alternately, if a chemical acts on the same cell that secretes it, it is an autocrine effector

Question 4

Types of Hormones:

Answer 4

The classic hormones fall into three categories

1) derivatives of tyrosine
2) derivatives of cholesterol (steroids)
3) peptides and proteins.

Hormones can also be classified based on their function.

Question 5

Peptide and Protein Hormones

Summary

Answer 5

a. The secretion of peptide and protein hormones follows the classical pathway for secretion of protein from cells.

b. After synthesis as a pre-prohormone on ribosomes from their respective mRNAs, the hormone is targeted to the rough endoplasmic reticulum.
i. Here the pre-prohormone is cleaved and the prohormone is transported to the Golgi apparatus where it is further processed and packaged into secretory vesicles.

c. The endocrine organ then secretes the hormone in response to specific signals by vesicular exocytosis, in a calcium-dependent manner.
i. A similar mechanism is used for the secretion of catecholamines like dopamine and epinephrine.

d. Once secreted into the bloodstream, the hormone is then carried to its target organ.

e. Most peptide and protein hormones (the exceptions are growth hormone, prolactin and Insulin-like growth factor) are transported in the blood as free hormones.
i. As the blood contains many proteases, the half-life of these hormones is therefore limited.

Question 6

Peptide and Protein hormone transport in blood

Answer 6

a. Once secreted into the bloodstream, the hormone is then carried to its target organ.
b. Most peptide and protein hormones (the exceptions are growth hormone, prolactin and Insulin-like growth factor) are transported in the blood as free hormones.
c. As the blood contains many proteases, the half-life of these hormones is therefore limited.

Question 7

How peptide/protein hormones are created

Answer 7

a. The secretion of peptide and protein hormones follows the classical pathway for secretion of protein from cells.

b. After synthesis as a pre-prohormone on ribosomes from their respective mRNAs, the hormone is targeted to the rough endoplasmic reticulum.
i. Here the pre-prohormone is cleaved and the prohormone is transported to the Golgi apparatus where it is further processed and packaged into secretory vesicles.

c. The endocrine organ then secretes the hormone in response to specific signals by vesicular exocytosis, in a calcium-dependent manner.
i. A similar mechanism is used for the secretion of catecholamines like dopamine and epinephrine.

Question 8

Steroid Hormone

Large Summary

Answer 8

a. The basic precursor for all steroid hormones is cholesterol.
i. Because the names of various steroid hormones derive from the numbering system of cholesterol, it is useful to know how the carbon atoms on a cholesterol molecule are numbered.

b. As steroid hormones are lipophilic and therefore membrane permeant, it stands to reason that their secretion will not be via the vesicular exocytosis as it is for protein and peptide hormones.
c. The steroid hormones are not stored in the cell they are synthesized in and are therefore immediately released into the blood stream.

d. Another consequence of their hydrophobicity is that they need to be carried by carrier proteins in the blood stream.
i. In the blood, steroid hormones exist in equilibrium between free and bound forms and at any given time only a small fraction of the hormone (1-5%) exists in the free form.

e. However, you must realize that it is the free form of the hormone that is biologically active and thus knowing total hormone levels in the blood might not be very informative.
i. The bound form serves as an essential reservoir of the hormone.

f. Unlike the protein and peptide hormones, steroid hormones linger in the bloodstream for a long time and have half lives in the order of many hours to days.

Question 9

Steroid Hormone- Hydrophobic nature in the blood stream

Answer 9

a. The steroid hormones are not stored in the cell they are synthesized in and are therefore immediately released into the blood stream.
b. Another consequence of their hydrophobicity is that they need to be carried by carrier proteins in the blood stream.
c. In the blood, steroid hormones exist in equilibrium between free and bound forms and at any given time only a small fraction of the hormone (1-5%) exists in the free form.
d. However, you must realize that it is the free form of the hormone that is biologically active and thus knowing total hormone levels in the blood might not be very informative.
e. The bound form serves as an essential reservoir of the hormone.

Question 10

Half-Life of the steroid hormone

Answer 10

a. Unlike the protein and peptide hormones, steroid hormones linger in the bloodstream for a long time and have half lives in the order of many hours to days.
b. Half-life of peptide/protein hormone is very short

Question 11

Measurement of Hormone levels:

Answer 11

a. Measurement of plasma levels of hormones is a primary tool of the clinical endocrinologist.

b. The two major methods for measuring hormone levels are
1) bioassays and
2) immunoassays.

c. Bioassays measure hormone activity and in this case hormone function is measured by using an exogenous system e.g. cell lines, to measure hormone activity.

d. Radio-immunoassays (RIA) and enzyme linked immunosorbent assays (ELISA) measure antibody binding to a specific region of the hormone.
i. They might not be useful if an abnormal form of the hormone is being secreted by the patient.

Question 12

Bioassays and Immunoassays for measuring hormone levels

Answer 12

a. Bioassays measure hormone activity and in this case hormone function is measured by using an exogenous system e.g. cell lines, to measure hormone activity.

b. Immunoassays—> Radio-immunoassays (RIA) and enzyme linked immunosorbent assays (ELISA) measure antibody binding to a specific region of the hormone.
i. They might not be useful if an abnormal form of the hormone is being secreted by the patient.

Question 13

Hormone Action

Protein and peptide hormones

Answer 13

a. When protein and peptide hormones (as well as some of the hormones derived from tyrosine, like epinephrine and norepinephrine) reach their target, they bind to specific receptors on the plasma membrane of the target cells.

b. Receptors for some hormones, e.g. epinephrine and norepinephrine, belong to the family of G-protein coupled receptors.
i. Binding of the hormone to these receptors results in changes in the levels of intracellular second messengers like cAMP, diacylglycerol and inositol phosphates.

c. Other hormones like growth hormone and prolactin have receptors that belong to the JAK/STAT family of receptors.
i. Activation of these receptors results in coupling and activation of a tyrosine kinase (Janus kinase or JAK), which then causes the phosphorylation of a group of proteins called signal transducers and activators of transcription (STATs).

d. Yet other receptors for hormones like Insulin and IGF-1 belong to a large family of protein tyrosine kinase receptors.
i. In this case the receptors themselves are tyrosine kinases that can be activated upon hormone binding.

e. Activation of catecholamine, protein and peptide hormones can have rapid consequences, like increased cytosolic calcium, exocytosis, phosphorylation of enzymes and ion channels.
i. In addition, they can have effects that are slower and involve changes in gene expression.

Question 14

Three Major Categories of Protein-Peptide Receptors

Answer 14

G-Protein Coupled Receptors, JAK/STAT receptors, Tyrosin Kinase Receptors

1. Receptors for some hormones, e.g. epinephrine and norepinephrine, belong to the family of G-protein coupled receptors.
   i. Binding of the hormone to these receptors results in changes in the levels of intracellular second messengers like cAMP, diacylglycerol and inositol phosphates.
2. Other hormones like growth hormone and prolactin have receptors that belong to the JAK/STAT family of receptors.
   i. Activation of these receptors results in coupling and activation of a tyrosine kinase (Janus kinase or JAK), which then causes the phosphorylation of a group of proteins called signal transducers and activators of transcription (STATs).
3. Yet other receptors for hormones like Insulin and IGF-1 belong to a large family of protein tyrosine kinase receptors.
   i. In this case the receptors themselves are tyrosine kinases that can be activated upon hormone binding.

Question 15

Steroid Hormone Action

Answer 15

a. Unlike the peptide hormones, steroid receptors are nuclear in their location.
b. Once steroid hormones reach their target cells, they enter the cell and bind to their receptors in the cytosol or the nucleus.
c. The receptor-hormone complexes then bind to specific hormone responsive elements (HRE) and activate transcription of specific genes

Question 16

Regulation of Hormone Secretion:

Answer 16

a. Levels of various hormones, metabolites, and minerals in the body are very tightly regulated around a specific set point.
i. This is achieved mainly by feedback loops.

b. There are two classes of these feedback loops.
i. One where the hormone level is the regulated variable and the other where the plasma concentration of a metabolite or a mineral acts as the regulated variable.

c. As you get into endocrine physiology, in detail, it will help you to understand these feedback loops and what the contribution of the target tissue is to this loop.
d. Target hormones regulating their own secretions usually go through negative feedback loops where excess of an end hormone acts to inhibit its own production

Question 17

Positive Feed Back Loops

Answer 17

a. Purely positive feedback loops are rare in biology for obvious reasons.
b. A positive loop will lead to an unstable and often cataclysmic process.
c. The only way a positive feedback loop can be terminated is by the exhaustion of the hormone or by an explosive event such as ovulation.

d. An example of a positive feedback loop in endocrinology is the production of oxytocin during the birthing process.
i. The stimulus for oxytocin secretion is the dilation of the uterine cervix.
ii. This dilation causes the release of further oxytocin thus creating a positive feedback loop that is terminated by the expulsion of the fetus and relaxation of the uterine muscles.

Question 18

Endocrine System

Answer 18

a. Effector cell releases substance into bloodstream, will be carried to target cell
i. this is one form of cell-cell signaling
ii. Hormones in this case are messengers that enter the blood

b. Paracrine signalling–> when effector cell secretes a molecule to a nearby target cell
i. does not cross blood, only interstitial space
ii. Example is somatostatin being released from S cells of pancreas to other tissue cells

c. Autocrine–> Effector cell will release messangers to self, target will be its own receptors

Question 19

Mechanisms will define what type of signalling a messenger will do

Answer 19

a. The mechanism is a hormone if it enters the blood stream
b. However, if it does not enter the blood, but goes to nearby cells, it will be paracrine
c. Many molecules can fall into multiple categories

Question 20

Classifying Hormones

Answer 20

a. Chemical Classification
1. Tyrosine–> Epinephrine, Norepinephrine, TH
i. Water-soluble molecules
2. Peptides–> Hypothalmic
i. Water-soluble molecules
3. Proteins–> Insulin, Growth hormone
i. Water-soluble molecules
4. Steroids–> Cortisol, sex steroids
i. NOT water soluble (hydrophobic)

b. Function Classification
1. Water and Mineral—> ADH (vasopressin), aldosterone

2. Energy–> Insulin, Growth Hormone
3. Growth—> Insulin like growth factor
4. Reproduction—> Estrogen, Testosterone

Question 21

How peptides/protein hormones are made

and tyrosine hormones

Answer 21

a. These hormones are stored in water vessicles, will be secreted via exocytosis
i. they are held in vessicles due to being water soluble

b. Increased intracellular Calcium is what causes exocytosis/secretion of the peptide/tyrisine hormones
i. It is called Ca2+ dependent exocytosis

c. These are created from the Nucleus, goes through the ER (and Golgi), then stored in vessicles

Question 22

How Steroid hormones are made

Answer 22

a. Steroid Hormones, upon creation, are not stored anywhere
i. they are hydrophobic

b. They will simply diffuse and leave the cell into the blood
c. Created from cholesterol

Question 23

Transporting Hormones in the blood

Answer 23

a. Peptide and protein hormones can travel in the blood due to being water soluble
i. They do not need carrier proteins
ii. however, they have short half-life due to high amount of proteases in blood

b. Due to high proteases in blood, protein and peptide hormones have short half-life, usually 15-30 min
i. no carrier proteins to protect these hormones

c. Steroid hormones are NOT water soluble, need to have carrier proteins
i. will have a binding protein that transport the steroid
ii. this means that steroid hormones have much longer half lives

d. Body cells can only utilize the unbound form of the steroid hormone!
i. this means that the small percent of unbound steroid can be picked up by cells
ii. this also means that there will be a longer half life

Question 24

Key thing with steroid hormones in the blood

Answer 24

1. There is always a large majority that are bound to the binding/carrier proteins
2. Only the small portion that is unbound can act upon cells, and is measured by the body
   i. the body will make adjustments on hormone based on the amount of free steroid hormone it measures

*remember, these rules only apply to steroid hormones

Question 25

How to measure hormone amount

Answer 25

1. Bioassay
   i. Measure based on hormone function
   ii. example: measure how much radio-labeled glucose gets taken up–> measure the amount of insulin
   
   • cannot acount for other hormones that cause glucose uptake
2. Immunoassays
   i. Radioimmunoassay (RIA)–> use radio-labeled hormone
   ii. Example: use radio-labeled insulin and an antibody that can bind to this insulin. Mix this with the subject’s non radio-labeled insulin. Can see how much antibody binds to the radio-labeled versus non-labaled
   iii. This allows for measuring more Exact amount of protein/hormone
   iv. does not measure function necessarily

ELISA- Type of Immunoassay

i. take serum from person, add a first antibody that will target the specific protein
ii. add second antibody that targets the first antibody, can see the 2nd antibody and measure the amount of protein
iii. Quick and accurate, just not measuring function as well

Question 26

Hormone Receptors: The different major types

Answer 26

a. Protein/Peptide and Tyrosine Hormones–> will bind to membrane receptors

Three major type of receptors for peptide:

1. G-Protein
   i. hypothalmic hormones
2. Cytokine Family
   i. Growth hormone, Prolactin
3. EGFR receptor family
   i. Insulin, Insulin like growth factor (IGF)

b. Steroid Hormones–> will bind to Intracellular Receptors
i. Cytoplasmic or Nuclear receptors

Question 27

Hormone Regulation–> Feedback mechanism

Answer 27

a. Hypothalamus—> Pituitary—> Target gland
i. Example: thyroid releasing hormone from hypothalamus—> causes thyroid stimulating hormone to reach the thyroid gland—> release thyroid hormone
ii. Thyroid hormone will cause Negative Feedback—> decrease TRH secretion from hypothalamus

b. Negative feedback is the predominant regulation of the body, positive feedback is RARE

c. Metabolites can also cause feedback (not just hormones)
i. Example: glucose
ii. when glucose is high, Beta cells will release insulin to lower glucose. When serum glucose is low, Glucagon will be released from alpha cells

Question 28

Pulsatile hormone release

Answer 28

a. Hypothalmic hormones are released in a pulsatile manner
b. Over time, there are sudden peaks of hormone release, than they will go back to a baseline
c. Hormone release is best controlled via pulsatile
d. Is happening even during Circadian Rhythem

Question 29

Circadian control of hormones

Answer 29

a. Circadian will have different peak amounts through the day that change
i. example is lower melanin during morning, higher at night
ii. still releasing many of the hormones in a pulsatile manner

b. Still use pulsatile release of hormones, its just that the peak of the pulsatile release will be lower or higher depending when in the day during the Circadian rhythm

Question 30

Pulsatile secretion

Answer 30

a. Pulsatile secretion is a biochemical phenomenon in which a chemical, such as a hormone, is secreted in a burst-like or episodic manner rather than constantly.
b. Examples of hormones that are secreted pulsatilely include gonadotropin-releasing hormone (GnRH) and growth hormone (GH).
c. Pulsatile secretion can be critical to hormone function, as evidenced by the case of GnRH agonists, which cause functional inhibition of the receptor for GnRH due to profound downregulation in response to constant stimulation.