What does IP3 do?

Inositol 1,4,5 triphospate

What are the three features of Nuclear Receptors?

Inactive Nuclear Receptor and ALL NUCLEAR RECEPTORS HAVE-DNA Binding Domain

Ligand Binding Domain

Transcription-Activating Domain

1.) Inositol (6) carbon just sitting around  with OH on every carbon

2.) PI KINASE comes and adds a phospate to carbon 4

3.)Then PIP Kinase comes and adds a phosphate to carbon 5

TURNS INTO PHOSPHATE INOSITOL 4,5 biphosphate which is a good substrate for phospholipase C

4.) YIELDS TWO PRODUCTS  1.)DIACYLGLYCEROL and 2.)IP3

5.) Diacylglycerol activates protein kinase C and IP3 releases calcium from the ER, the calcium from ER goes on to complete the activation of protein kinase C

1.) An activated nerve terminal releases acetylcholine

2.)Acetylcholine binds to receptor in the endothelilal cell.

3.) This activates NITRIC OXIDE SYNTHASE

4.)Nitric oxide synthase acts upon arginine

5.)There is a diffusion of Nitric oxide from endothelial cell towards Smoothe muscle cell.

6.) In the muscle cell NO binds to guanylyl cyclase

7.) GTP converted to cyclic GMP

8.)LEADING TO RAPID RELAXATION OF SMOOTH MUSCLE CELL

Hormones are..?

Their concentration is..?

Their Specificity is related to..?

Hormones are organic compounds synthesized in glands & secreted into blood & transported to target cells.

They act at LOW concentration

Their specificity is related to production of receptors by target cells.

1. Progesterone

2.Androgens

3.Estrogens

4.Corticosteroids

"PACE"

ACTH

TSH

MSH

LH

FSH

Growth Hormone

Insulin

Glucagon

Name 2 Amino Acid Derivatives

and the type of receptor each has

Catecholamines-cell surface receptor

Thyroid Hormones-nuclear receptor

Steroid Hormones

Retinoic Hormones

Thyroid Hormones

Ligands of Peroxisome proliferator-activated receptors (PPARs)

Second messenger CYCLIC-AMP......

stimulate/inhibit adenylate cyclase

Stimulate glucagon, beta-adrenergic, catecholamines, ACTH, parathyroid hormone, TSH

INHIBIT--> alpha-2 adrenergic catecholamines, acetylcholine, somatostatin

For

Atrial Natriuretic factor (ANF) and Nitric Oxide  the second messenger is

For

Insulin

Growth Hormone

Prolactin

Erythroprotein

Growth Factors

the Second Messenger is...?

For ADH

Gastrin

Oxytocin

Thyrotropin-releasing hormone the second messenger is..?

1.) Signaling by phosphorylation

2.)Signaling by GTP-Binding protein

Signal binds to transmembrane protein.

conformational change allows the G-protein to move closer

The GDP on inactive G-protein comes off and GTP binds to the alpha subunit.

The alpha subunit now deattaches from the other two subunits of G-protein which are also activated.

The alpha subunit can activate a target protein.

Then hydrolysis of GTP by the alpha subunit inactivates the subunit it falls off from the target protein and binds back with the other two subunits.

The target protein is inactivated and the G-Protein goes back to its inactivated form.

• Calcium binds to calmodulin
• Once calcium is bound to calmodulin then that combiniation can bind to an inactivated protein kinase.
• That protein Kinase  then becomes actiavted, but that protein kinase can be further actiavted following a cell phosphorylation and now it will be FULLY ACTIVE.

Overtime when the calcium concen goes down then the calcium molecules will dissassociate from the calmodulin, and calmodulin will fall off from protein kinase.

The protein kinase will still retain some activitiy as long as it has that phosphate. 

So the action of protein phosphatase is to remove the phosphate from the protein kinase which will now inactivate the protein kinase by diactivating the CATALYTIC DOMAIN.

JAK-STAT SIGNALING

what stimulates it?

Events?

Final function?

Factor that stimulates JAK-STAT signaling is alpha-interferon

• Once interferon is bound to the alpha interferon receptor
• There is a cross-linkage of adjacent receptors
• The JAKS (tyk2 and jak1) cross-phosphorylate each other on tyrosine
• The actiavted JAKS then go on to phosphorylate receptors on tyrosine.
• Then STATs come along and dock on to specific phosphotyrosines on receptor.
• The Jaks phosphorylate them
• The STATs dissociate from the receptor and dimerize via SH2 Domain
• The Stats then migrate to nucleus they bind to DNA and other gene regulatory proteins
• TARGEt GENER TRANSCRIPTION takes place

TGf-Beta (transforming growth factor beta) dimer binds to its receptor (TYPE II) 

The binding allows the TYPE II receptor to recruit and phosphorylate a TYPE-I receptor.

The phosphorylated type I receptor recruits and phosphorylates Smad2 OR Smad3

The smad2/3 which was phosphorylated dissociates from the receptors and oligomerizes with Smad4

The smad2/3-smad4 Oligomer migrates to nucleus, recruits other gene regulatory proteins, and activates transcription of specific targer genes.

TARGET GENE TRANSCRIPTION

Notch

Wnt

Hedghog

NF-KB Pathways

• Wnt protein binds to receptor
• Dishevelled is actiavted
• That blocks the action of protein kinase
• B-Catenin is no longer phosphorylated so it will not be broken down it is stablized.
• The stablized B-catenin will migrate to nucleus and displace the GROUCHO
• Lead to turning on Wnt-Responsive genes.

• Examples include activation of protein kinase C which has multiple targets-increased profileration
• Another example is the calcium-calmadulin dependent protein kinase

They both involved protein kinases but Jak-stat used tyrosine specific kinase and Smad uses serine/threonine specific kinase.

They also involve the phosphorylation of some associated proteins which migrates to nucleus and bound to response elements and turned on genes.

True or False

Signaling can be silenced by action of tyrosine phosphates

PDGF and FGF

FGF-initially interacts proteoglyan glycosaminoglyan chain and then it interacts with the FGF receptor which will go onto phosphorylate the receptor side chain

PI 3-Kinase

GTPase-activated Protein (GAP)

Phospholipase C-y (PLC-y)

SH2 binds to activated PDGF

RAS in MAP kinase signaling

There is a protein kinase cascade

Binding of growth factor to its receptor
Leads to activation protein kinase (tyrosine kinase activity)
Grb-2 adaptor protein helps set things in place
Grb-2 binds to tyrosine phosphate
leads to Ras GEF to make RAS protein active by adding GTP to it
Active Ras Protein goes onward and there is transmission of signal along multiple pathways..

Then the active RAS activates RAF (Map-Kinase-Kinase-Kinase)

RAF will go onto activate Mek (Map-Kinase-Kinase)

Mek will activate Erk (Map-Kinase)

This all leads to CHANGES IN PROTEIN ACTIVITY and CHANGES in gene expression