- a steriod hormone

1. diffuses passively across the plasma membrane

2. binds to a receptor protein in cytosol or nucleus

3. the hormone-receptor diffuse across the NPC

4. binds to response elements on promotors & enhancers (stimulates transcription)

- steriod hormones

- thryoid hormones

- retinoic hormones (vitamine A)

- calcitriol (Vitamine D)

1. hormone binds to receptor which cause a conformation change

2. 2nd messenger bind to other cellular parts

-Cyclic AMP

-synthesized from ATP & degraded to AMP

- synthesized from ATP by adenylyl cyclase 

- synthesized from cAMP by cAMP           phosphodiesterase

- rxn is reversibel

- it inactivates the cAMP phosphodiesterase 

- you will have increased amounts of cAMP

- gives you diarrhea

1. hormone binds and changes the conformation

2. protein loose affinity of GDP thus gaining GTP

3. The α subunit with bound GTP separates from β & γ subunit thus activating it.

4. α subunit binds to adenyl cyclase making cAMP

5. cAMP binds to the regulatory subunit of protein kinase A (activates it)

6. the 2 catalytic subunits are cleaved off

7. PKA phosphorylates CREB - response element that activates transcription

- contains a α, β, & λ units

- α has binding sites for GDP and GTP

- active G-protein: has GTP bound

- inactive G-Protein: has GDP bound

- phosphorylates CREB

- a response element

- this activates transcription

- cAMP can be increased or decreased by hormone

- G_sα-protein is activated thus increasing cAMP

- G_iα-protein is activated thus decreasing cAMP

- TPH (parathyroid hormone) raises blood Ca level by raising cAMP

- Abnormalities

     * sign of PTH deficiency (hypocalcemia, tetany)

     * causes: mutation in the PTH receptor

  -abnormal G_sα making insufficient coupling adenylate cyclase

- TSH (thyroid stimulating hormone) from the pituitary gland stimulates hormone by raising cAMP

- Problem

* benign tumors in thyroid gland can over produce the hormone

- Cause:

1. activated somatic mutation in the gene

2. a G_sα mutation (accumulation of cAMP)

- cause of diarrhea 

- binds to G_sα and inactivate hydrolysis of GTP

- leaves protein in permanent active state

- you get an accumulation of cAMP

action

- uses NAD to attach nicotinamide to g-protein

treatment

- opium to inhibit diarrhea 

aka "whooping cough"

- it binds to G_iα protein and inhibits it

- G_iα cant stop the G_sα from making cAMP

- you get an accumulation of cAMP

1. phosphatidylinositol (PI) is phosphorylated by PI kinase using ATP

2. it undergoes another phosphorylation by PIP kinase using ATP

-structure is split by PLCβ giving a DAG (left in PM) + an inositol portion (IP₃) thats hydrophilic

3. DAG binds to Protein kinase C (PKC)

4. IP3 releases Ca from ER which activates PKC

- increased Ca causes relaxation

- produces NO (nitrous oxide) that bind to guanylate cyclase

- inhibits the cGMP phosphodiesterase

- accumulating more cGMP 

- Protein Kinase C: activated by DAG + Ca

- Calmodulin: activates smooth muscles

- Troponin C: activates skeletal and cardiac

1. GTP to cGMP by enzyme guanylate cyclase

2. cGMP to GMP by cGMP phosphodiesterase

***note guanylate cyclase activated in 2 forms

1. membrane-bound guanylate cyclase by hormones

2. cytoplasmic guanylate cyclase by NO

- ANF receptor is a ligand-activated guanylate cyclase

- ANF binds to ANF receptor activating PKG

- PKG relaxes smooth muscles

Mechanism of Growth factors receptors 

(tyrosine K)

1. dimer binds on tyrosine kinase causing receptors to cluster & phosphorylate each other

2. undergoes a conformational change and autophosphorylates (SH2 domain)

1. growth factor binds to receptor

2. it undergoes autophosphorylation

3. next it binds onto phospholipase C-γ

-PLCγ phosphorylates PIP2 making IP3

**Note: PLCβ is activated by G-proteins

1. Growth factor binds to Tyrosind K

2. it undergoes autophosphorylation

3. it activates IP3 kinase which makes PIP3

4. PIP3 attracts proteins PDK1 & Akt which activates protein kinase B (PKB)

5. PDK1 & mTOR phosphorylates & activates Akt

6. Akt dissociates (active form)

- RAS has only one subunit w/ GDP bound

- MAP kinase activates small G-protein Ras

- upon activation it gets a GTP that will lead to protein kinase cascade

- this is an important target for cancer mutations

- similar to growth factors except:

       * receptor is a disulfide-bonded tetramer

- mediated by IRS-1 & IRS-2

  *if one receptor is missing = Leprechaun or Dorphism

1. insulin binds to TK which undergo autophosphorylation

2. insulin substrate (IRS-1) binds & become tryosine-phosphorylated

3. SH2- containing proteins bind signaling other proteins to bind

Desensitization of G-Protein Coupled

Receptors

1. stimulated (unstimulated) receptor becomes phosphorylated

2. uncouples receptor from G-protein + BARK attracts arrestin

3. Arrestin binding cause: 

a. receptor sequestration (receptor is recycled)

b. receptor down-regulation (receptor is not recycled)

- sent to lysosome