Term
Overview of the classical phosphatidyl inositol pathway
|
|
Definition
1. The activated receptor activatesa trimeric G protein called Gq
2. Gqa activates phospholipase C-b
3. Phospholipase C-b cleaves PIP2 to form DAG and IP3
|
|
|
Term
The structure of the two second messengers derived from PIP2 by the action of phospholipase C-b |
|
Definition
DAG- -very nonpolar, remains membrane bound. ACTIVATES PKC
IP3- Soluble
-very high density of
negatively charged and polar groups.
- diffuses through cytosol
RELEASES CALCIUM FROM ER
|
|
|
Term
|
Definition
•rapidly diffuses through the cytoplasm.
• induces the rapid release of calcium from intracellular stores
-endoplasmic reticulum
-sarcoplasmic reticulum (smooth muscle)
•The IP3-gated calcium release channels are regulated by a positive feed back mechanism - calcium binds back to the channels to increase the calcium release.
|
|
|
Term
Three mechanisms terminate the initial calcium response |
|
Definition
Termination of the response
1. The lifetime of IP3 in a cell is very short:
IP3 is rapidly dephosphorylated and inactivated.
2. Some IP3 is phosphorylated (forms inositol 1,3,4,5 tetraphosphate (IP4); promotes refilling of the intracellular calcium stores.
3. The calcium that enters the cytosol is rapidly pumped out of the cell.
|
|
|
Term
DAG couples receptor activation to protein kinase C (PKC) |
|
Definition
DAG has two potential signaling roles
1. Can be cleaved to release arachidonic acid
-messenger
-used to synthesize eicosanoids
prostaglandins-pain, inflammation
2. Activates protein kinase C (PKC) (major function)
-serine/threonine kinase
-activation requires calcium and DAG (called conventional PKC enzymes when activated by both DAG and calcium)
-conventional PKC enzymes; alpha, beta, and gamma
-knockouts in mice reveal unique phenotypes
|
|
|
Term
Mechanism of Protein Kinase C (PKC) activation by DAG and calcium |
|
Definition
-IP3-induced rise in cytosolic calcium
-calcium binds to PKC-altered confirmation
-PKC translocates from the cytosol to the
cytoplasmic face of the plasma membrane
-PKC binds to DAG and is activated.
|
|
|
Term
|
Definition
-polycyclic alcohol derivatives
- carcinogenic (tumor promoters)
-activate Protein Kinase C
- mimics diacylglycerol
- not readily degradable
- the activation is persistent.
|
|
|
Term
Ca2+ is a universal regulator of intracellular signaling |
|
Definition
-Contraction
-Proliferation
-Fertilization
-Learning and memory
-Secretion
-Vesicle trafficking
-Cell proliferation
-Metabolism
|
|
|
Term
The EF hand protein calmodulin serves as a Ca2+ sensor. |
|
Definition
Calmodulin
-Found in all eukaryotic cells
-Multi-functional calcium receptor
-Up to 1% of total protein mass
-consists of two globular lobes joined by a long alpha helix.
-Each lobe contains two EF hands. There are 4 calcium binding sites (shown as 1, 2, 3, and 4.)
|
|
|
Term
What are calmodulin’s targets? |
|
Definition
1.plasma membrane Calcium-ATPase pump 2
2.multifunctional calmodulin-dependent protein kinases (CaM Kinase)
3. calcineurin
|
|
|
Term
The cAMP and Ca2+ pathways interact |
|
Definition
Ways in which the pathways interact:
1. Some forms of cAMP phosphodiesterase and adenylyl cyclase are regulated by Ca++/calmodulin.
2. Share downstream targets
Example: CaM-kinases can phosphorylate CREB at a different site than that phosphorylated by PKA.
|
|
|
Term
Calcineurin, a calmodulin target, is a Ca2+ regulated protein phosphatase. |
|
Definition
Calcineurin
•Only serine/threonine protein phosphatase under the control of calmodulin
•calmodulin binding leads to a conformational change in calcineurin that moves the autoinhibitory domain of calcineurin away from the catalytic site.
|
|
|
Term
Role of calcineurin in NFAT activation |
|
Definition
•NFAT is held inactive in the cytoplasm
•A calcium signal activates calcineurin
•Result
1. Dephosphorylation of NFAT
2. nuclear translocation
3. increased affinity for DNA
|
|
|
Term
|
Definition
Immunosuppresive drug used in transplant surgery patients.
-It is currently one of the most useful drugs
of its type.
-Inhibits calcineurin by blocking the active site of calcineurin and preventing it from acting on any molecules within the cell.
-major consequence is the inhibition of NFAT activity, thus preventing the rejection of foreign organs or bone marrow by disrupting the signaling pathway that activates T cells.
|
|
|
