Lecture 1 - Cell and molecular physiology

Question 1

What are 3 main components of CLASSIC endocrine glands?

Answer 1

1. ductless
2. Secrete hormones DIRECTLY into the bloodstream or EC
3. Entire organ is dedicated to endocrine function

Question 2

What are the 7 classical endocrine organs?

What is the exception?

Answer 2

1. Pineal Gland - sits on the epithalamus  technically outside of the BBB  can respond to peripheral signals
2. Pituitary gland
3. Parathyroid (calcium & phosphate regulation)
4. Thyroid gland
5. Adrenal Gland
6. Pancreas
7. Ovary
8. Testes (gonads)
9. PLACENTA - considered endocrine during fetal development

PANCREAS is the exception since it is both endocrine & exocrine

Question 3

What are the 6 NON-classical endocrine organs?

Answer 3

Brain – especially hypothalamus (“releasing hormones”)

Kidney – Renin, Vitamin D, erythropoietin (EPO)

Heart – atrial/brain natriuretic peptide (ANP, BNP)

Liver – Insulin-like growth factor
(IGF-I)

GI – small intestine, stomach (serotonin, ghrelin)

Adipose Tissue - leptin

Question 4

What are 2 key concepts in homeostasis?

Answer 4

HYPER = overproduction of a hormone and/or hypersensitivity
(at the receptor level or receptor signaling pathway) to hormonal effects

HYPO = underproduction of a hormone and/or insensitivity to hormonal effects.
(ex: insulin resistance - body no longer responding)

Question 5

What organ is a good example of integration?

Name the 6 organs that affect this

Answer 5

THYMUS

1. Cortisol/adrenalin from ADRENAL glands
2. Thyroid hormones from thyroid gland
3. GH/GnRH from CNS
4. Testosterone
5. Grhelin - Stomach
6. Leptin/Adipokinase - Adipose tissue

Question 6

How are endocrine pathologies characterized?

Why are they often difficult to characterize?

Answer 6

Characterized by a hormone imbalance

Defect can be in classical endocrine gland (primary defect) or other organ (secondary/tertiary)

Symptoms can be vague and hard to diagnose
Weight/Appetite changes
Fatigue
Hair loss/Hirsutism
Cognitive (forgetfulness/confusion)
Dizziness
Moodiness (depression/anxiety/aggression)

Symptoms can take a long time to develop and might seem unrelated

Question 7

What is an example of a CONGENITAL endocrine pathology?

What causes it?

What are the 3 symptoms?

Answer 7

CRETINISM

1. Iodine deficiency during development
2. Short stature/impaired bone formation
3. Mental retardation
4. Delayed motor development

Question 8

What is MEN (Multiple Endocrine Neoplasia)?

Is this an genetic or congenital pathology?

Answer 8

Multiple Endocrine Neoplasia (MEN)

characterized by 2-3 tumors in multiple endocrine glands

(parathyroid, pituitary, entero-pancreatic)

Question 9

State some examples of the following categories of endocrine pathologies:

1. Malignant and benign tumors
2. Infections/immunological problems
3. Environmental Factors

Answer 9

1.Neoplastic tissues
Small lung cell carcinoma

2. Autoimmune – Diabetes Mellitus Type
3. PCBs, DES, birth control
   - either compete for receptor or change how hormone delivered to cells

Question 10

State examples for the following endocrine pathologies:

1. Trauma/ Stress
2. Surgical
3. Therapeutic

Answer 10

1.Trauma/stress:

Sheehan’s Syndrome – postpartum hemorrhage/shock; results in massive pituitary cell death
(SMALL GROUP)

2. Surgical
   Thyroid gland removal (often parathyroid injury)

3.Therapeutic:
Glucocorticoid therapy (Crohn’s disease and others)

Question 11

What is Diabetes mellitus highly correlated with?

Answer 11

Highly correlated with OBESITY

• correlated with BMI

Question 12

What are the 3 main mechanisms of hormone action? How do they function?

Answer 12

1. Endocrine
   – hormones secreted into the blood acting on downstream target tissues.
2. Paracrine
   – hormones secreted into the interstitial space acting at nearby cells.  can be at a synapse (considered a NT)
3. Autocrine – hormones secreted into the interstitial space acting back on same cell.

Question 13

______ binds to hormones to facilitate transport.

They generally increase what of the hormone?

What type of hormones uses them most often?

Answer 13

1. Hormone Binding Proteins
2. Increase the HALF - LIFE of the hormone
3. Mostly for STEROID hormones (lipophilic)
   Also: IGF-I, GH, T4/T3

Question 14

If the hormone is bound/unbound there is action in the cell. (choose one)

Answer 14

UNBOUND

• only free hormone has action

Question 15

What do the following have in common? What do they bind?

1. Sex hormone binding globulin (SHBG)
2. Corticosteriod binding globulin (CBG)
3. Thyroxine binding globulin (TBG) and transthyretin (TTR)

Answer 15

1. Sex hormone binding globulin (SHBG) – binds estrogens and testosterone
2. Corticosteriod binding globulin (CBG) – binds cortisol/corticosterone
3. Thyroxine binding globulin (TBG) and transthyretin (TTR) – binds thyroid hormone

Question 16

What is an example of a nonspecific hormone binder?

Answer 16

ALBUMIN

• binds most lipophilic compounds in blood
• weak interaction

Question 17

Why is albumin bound SHBG (sex hormone binding globulin) considered bioavailable?

Answer 17

Since the bind to albumin is easily broken, it is considered bioavailable if present in the blood

Question 18

How are extracellular hormones delivered to the target?

Answer 18

Scenario #1 –
1. Bound Steroid hormone is released at membrane.

2. Freely diffuses across lipid bilayer. (lipid soluble)
3. Finds intracellular targets.
   - FREE INSIDE THE CELL

Question 19

What is the second scenario of hormone delivery to the target?

Answer 19

Scenario #2 –

1. Hormone/protein complex binds to MEGALIN. (both hormone & HBP)
2. Formation of ENDOCYTIC vesicle.
3. Hormone dissociates and is released from vesicle.

Question 20

What structure forms an endocytic vesicle when delivering hormones to the target?

Answer 20

MEGALIN

Question 21

If there is no _____ there is no action.

Answer 21

RECEPTOR

Question 22

The receptor determines what 2 important functions of the hormone?

Answer 22

1. DURATION of hormone activity

2. AUTOREGULATION by hormone itself (up/downregulation depending on hormone levels)

Question 23

Hormones bind to receptors with high _____ and high _____

Answer 23

1. Affinity

2. Specificity

Question 24

What is the difference between affinity and specificity?

Answer 24

Specificity: being able to distinguish between similar substances

Affinity:
measured as Kd
- Kd= ligand concentration that occupies 50% of binding sites

Specificity:
Ki = ability to displace ligand at 50% of max capacity

Question 25

If the Ki is smaller, is the specificity greater or less?

Answer 25

GREATER SPECIFICITY | - not able to displace the ligand

Question 26

You must reach Kd in order to get a response. True or False?

Answer 26

FALSE - you do not need to reach Kd to get a response

Question 27

What did the Binding assays for estrogen related receptor (ERR) and ligand (4-OH tamoxifen) show? Was the Ki low or high for 4-OHT?

Answer 27

Showed that both DES and TAM bind, but 4-OHT shifted left, so indicated a specificity for 4-HT LOW Ki for 4-OHT showed that there was specificity for 4-OHT - adding increased amounts of hormone showed that at a certain Ki the hormone was kicked off and competitively bound by 4-OHT

Question 28

What tells you nothing about action: Affinity or Specificity?

Answer 28

AFFINITY | - only shows that a hormone can bind (Kd shows how much bound at 50%)

Question 29

What are 4 examples of Liphophobic receptors? What do they bind? What 2nd messaging pathways are they coupled to?

Answer 29

1. ION CHANNELS 2. Intracellular signalling - G protein 3. Receptor- Linked Kinase 4. Receptor Kinase - they are coupled to second messenger signaling pathways (cAMP, IP3/DAG) **rapidly internalized or degraded**

Question 30

Ion channels are not receptors, true or false? What typically activates ION channels?

Answer 30

TRUE - not receptors, but have receptors that open the channels nearby 1. Ligand binding causes conformational change that opens channel - Neurotransmitters typically activate these types of receptors

Question 31

G protein Lipophobic receptors are mostly bound by what 2 things? What does ligand binding activate?

Answer 31

1. Proteins & PEPTIDE HORMONES | 2. Activates second messenger signaling cascades

Question 32

Which Cell surface lipophobic receptor does not have intrinsic catalytic activity?

Answer 32

RECEPTOR Linked KINASES

Question 33

Ligand binding in Receptor-linked Kinases causes what? What are some examples? (3)

Answer 33

1. DIMER FORMATION - activates intracellular kinase ex: 1. Growth Hormone (GH) 2. prolactin 3. erythropotein

Question 34

Which one has intrinsic catalytic activity: 1. Receptor Kinases 2. Receptor - linked Kinases

Answer 34

RECEPTOR KINASES phosphorylate themselves when the ligand binds - phosphorylated residues serve as scaffolds

Question 35

What two hormones utilize Receptor kinases?

Answer 35

INSULIN & ANP

Question 36

What is the difference between lipophilic and lipophobic receptors?

Answer 36

LIPOPHILIC - bind mainly INTRACELLULAR receptors

Question 37

Which type of hormone receptors often: 1. bind large CHAPERON proteins in cytoplasm (heat shock) 2. Require SLOW biological response (transcription/translation) 3. Can repress or activate transcription?

Answer 37

LIPOPHILIC

Question 38

Which types of receptor (lipophilic/lipophobic) is considered a transcription factor?

Answer 38

LIPOPHILIC

Question 39

What is an example of a LIPOPHILIC hormone?

Answer 39

THYROID HORMONE - not steroid, but bind nuclear receptors already present in the cell

Question 40

When the lipophilic receptor is NOT bound to a ligand, transcription is active. True or False?

Answer 40

FALSE When receptor is NOT bound to ligand = transcriptional repression Ligand (thyroid hormone) binding activates gene transcription