Signal transduction by protein hormones

What is a hormone

Chem regulatory subst secreted by ductless glands (Endocrine glands)

Passes through bloodstream to reach target tissues which contains specific receptor of that hormone

What are hormone receptors and the 2 types based (on location)

Hormone receptors are cell associated recog proteins.

1. Cell (plasma) membranes receptors

2. Intracellular receptors (Cytosol/Nucleus)

3 types of Hormones based on chemical nature

1. Protein hormones

2. Amino acid derived hormones

3. Steroid hormones

Types of protein hormones

List

1. Large polypeptides

2. Small polypeptides

3. Glycoproteins

1. Large polypeptides = Insulin , Glucagon

2. Small polypeptides = ADH , Oxytocin

3. Glycoproteins = FSH , LH

Types of Amino acid derived hormones

Thyroid hormones & catecholamines —> derived from Tyrosine

Melatonin —> derived from Tryptophan

What are steroid hormones derived from and its types

Steroid hormones derived from cholesterol (makes them Lipophilic & bound to carrier proteins)

1. Glucocorticoids

2. Mineralocorticoids

3. Sex hormones (Progesterone, Testosterone, Estrogen)

How are hormones classified by action mechanisms

1. Hormones that bind to memb receptors (Protein/Amino acid ( besides thyroid hormones)

2. Hormones that bind to intracellular receptors (Steroid hormones + Thyroid hormones)

Characteristics of hormones that bind to intracellular receptors and name key examples

1. Lipophilic hormones

2. Need transport proteins to reach target tissue

3. Long plasma ½ life (hrs to days)

4. Action mediated by forming hormone-receptor complex.

Hormones that bind to intracellular receptors

Hormones include:

1. Steroid hormones

2. Thyroid hormones

3. Calcitirol (active Vit D)

4. Retinoids (vit A derivatives)

Mechanism of Action of hormones bind to intracellular receptors

1. Hormone diffuse across target cell plasma memb

2. Binds to specific cytosol like steroid hormone/ nuclear like thyroid hormone receptor

3. —> forms hormone receptor complex

4. hormone receptor complex accumulates,dimerizes and binds to HRE (on DNA)

5. Causes promoter activation/inhibition and ↑/↓ transcription of targeted gene (depending on the hormone)

Define HRE

Hormone response element is a specific regulatory DNA sequence (its on DNA)

Characteristics of Hormones which bind to cell membrane receptors

1. Hydrophilic hormones

2. Dont need transport proteins to reach target tissues

3. Short plasma ½ Life (mins)

4. Action mediated by second messenger

What is second messenger and the examples

Second messenger is intracellular signal produced when hormones (1st messenger) bind to its specific cell memb receptor on target cell. It amplifies signal and mediates effects of the hormone.

Examples

1. cAMP (Cyclic adenosine monophosphate)

2. cGMP (Cyclic guanosine monophosphate)

3. Calcium / phoshpatidyl inositol

4. Protein kinase cascades

cAMP pathway steps

1. Hormone bind to specific cell memb receptor (on target tissue)

2. Binding cause GDP + G protein —> activates Gs protein (GTP + G protein)

3. Active G protein —> activates/inhibits adenylate cyclase enzyme

4. Adenylate cyclase enzyme (if active) causes active G protein —> GDP + Pi and ATP—> cAMP

5. cAMP —> Activates PKA/ binds to CREB

6. Hormone effects mediated

7. cAMP hydrolysed by phosphodiesterase into AMP to terminate cAMP

Hormones that activate and inhibit adenylate cyclase enzyme

Activate

1. FSH, LH, TSH, HCG

2. Glucagons

3. B catecholamines (epinephrine/norepinephrines)

4. PTH and calcitonin (Ca2+ homeostasis)

Inhibit

1. Somatostatin

2. Angiotensin II

3. a2 catecholamines

What effects does cAMP mediate on cells and how

Affects:

1. Neuronal funct

2. Muscular contraction

3. Secretion

4. Growth and differentiation

5. Immune mechanisms

cAMP mediates effects by mechanisms:

1. Protein Kinase (PKA)

2. Gene expression (CREB)

Protein Kinase characteristic and what it does on activation?

• cAMP dependent protein kinase is an inactive R2C2 tetrameter

• (2 regulatory subunits [R] , 2 catalytic subunits [C])

1. On activation 4 cAMP bind to 2 R subunits leaving 2 C subunits free to act

2. Active protein kinase transfers phosphate group from ATP to serine or threonine amino acid residues of specific protein causing its phosphorylation

3. Phosphorylated protein (eg:enzyme) mediates hormonal effect

How does cAMP do Gene expression?

1. cAMP bind to cAMP response element binding protein.(CREB protein)

2. cAMP + CREB protein complex bind to specific HRE on DNA —> affect gene transcription

3. This affects amount of specific protein —> mediates hormonal effect

What does Phosphodiesterase do and what inhibits it?

After medicating hormonal effects cAMP hydrolysed by cAMP dependent phosphodiesterase enzyme into 5’AMP.

Phosphodiesterase inhibited by methyl xanthines (eg: caffeine)

what is Cyclic GMP (cGMP) and what does it cause

Def: cGMP is 2nd messenger of Atriopeptins (hormone group) eg: ANF/ANP

(ANF = Atrial natruiuretic factor)

They cause:

1. Natiuresis (Na excretion)

2. Diuresis (Urine production)

3. Vasodilation

4. Inhibition of aldosterone (adrenal gland) secretion

cGMP pathway steps

1. Hormone binds to its specific receptor —> Activates memb bound guanylate cyclase

2. Active guanylate cyclase catalyses formation of cGMP from GTP

3. cGMP activates cGMP-dependent protein kinase

4. Active protein kinase phosphorylates proteins

5. Phosphorylated proteins mediate effect of atriopeptins

6. After medicating effect cGMP hydrolysed by cGMP dependent phosphodiesterase enzyme 5’GMP

Which compounds stimulates soluble cytosolic form of guanylate cyclase? and cause what?

Compounds

1. Nitric oxide

2. Nitroglycerine

3. Nitroprusside

4. Sodium azide

5. Sodium nitrite

Stimulate soluble cytosolic form of guanylate cyclase causing:

• Smooth muscle relaxation

• Vasodilation

Which hormones use Calcium or Phosphatidyl inositols

1. Gonadotropin releasing hormones (GnRH)

2. Thyrotropin releasing hormone (TRH)

3. Vasopressin/Antidiuretic hormone (ADH)

4. a1 adrenergic catecholamines

Calcium or phosphatidyl inositols pathway steps

1. Hormone binds to its specific receptor —> activates Gq protein

2. Active G protein activates phospholipase C enzyme (PLC) **

3. Active PLC hydrolyses phosphatatidyl inositol 4,5 biphosphate (PIP2) → 1,2 Diacyl glycerol (DAG) or Inositol triphosphate (IP3)

4. DAG —> activates protein kinase C —> active PK C phosphorylates specific substrates (eg:enzymes) —> mediates hormone effect

4. IP3 —> releases Ca2+ from intracellular storage sites (mitochondria, ER) —> Ca2+ acts as second messenger.

** GTP —> GDP (inactive) + pi

Protein Kinase cascade: What is Tyrosine kinase and where can it be found?

Tyrosine kinases is a group of enzymes which phosphorylates their substrates on tyrosine residue —> become activated

Tyrosine kinase may be

1. Intrinsic part of receptor (eg: Insulin receptor)

2. Intracellular associated with receptor but not intrinsic part of it

How does Insulin receptor work (receptor with intrinsic tyrosine kinase)

1. Binding of hormone to its receptor

2. —> tyrosine kinase activation

3. —> receptor autophosphorylation

4. —> Phosphorylates Insulin receptor substrates (IRS) on tyrosine residues

5. —> Phosphorylated IRS activates PI3-kinase or MAP Kinase Cascade

6. Active Phosphatidyl inositol 3 kinase (PI3-kinase) activates numerous molecules which mediates effects of hormone

6. Mitogen activated protein kinase cascade (MAP kinase cascade): Phosporylated IRS cause cascade activation: RAS → RAF → MEK → MAP kinase Active MAP kinase affects certain transcription factors & ribosomal subunits → mediate effect of hormone

Remember: MAP kinase cascade Is a cascade system (series of reactions where 1 enzyme affects the next…etc)