L19: Cell Signaling II Flashcards
what are the two major types of receptors?
-intracellular (Steroid hormones)
-cell-surface receptors
three classes of cell-surface receptors
- ion-channel-coupled receptors
- G-protein coupled receptors
- enzyme-coupled receptors
ion-channel-coupled receptors
- Causing a change of the permeability of the plasma membrane to specific ions, thus a change of membrane potential
- Very rapid responses (within milliseconds)
- Especially important in nerve cells and muscles cells
open/close depending on signal
difference in charge occurs due to flow of ions
G-protein coupled receptors
GPCR -> G protein -> Targets -> Responses
how are GPCRs used in everyday applications?
targeting signaling pathways to treat disease
~1/3rd of drugs in use today work through GPCRs
GPCRs
- Most numerous class of receptors (>700 in humans)
- Can be activated by a wide variety of signaling molecules
GPCRs have a similar structure
GPCRs activate G proteins - what are G proteins?
- These G proteins have three subunits
(trimeric): a, b, g - They are different from the monomeric small
G proteins (Ras, Ran, Rab, etc) - They are tethered to the plasma membrane
what happens when a signal binds to a receptor
- Signal binding causes a conformational
change in the receptor that is transmitted
to its cytoplasmic domain - Activated receptor acts as a GEF for its G-protein
- Activated Ga and Gbg can each
activate different effector proteins - Once activated, a GPCR can activate
many molecules of G protein
G proteins activate membrane-bound enzymes that produces small messenger molecules (what are the two major targets?)
two major targets of GPCRs:
-phospholipase C (PLC) - produces certain lipids
-adenylyl cyclase - generates cAMP -> activates PKA (Protein Kinase A) -> cellular responses
phospholipase C leads to the production of two small messenger molecules
secondary messenger molecule IP3 can lead to the release of Ca+2 from the ER, thus increasing the cytosolic Ca+2 level
fertilization of an egg by a sperm triggers… and leads to….
an increase in cytosolic calcium level in the egg
sperm-egg contact activates a PLC in the egg
increased Ca2+ leads to:
-physical changes of the egg shell to prevent
more than one sperm from entering the egg
-Activation of the egg so that embryonic
development is initiated
DAG, in combination with Ca 2+, can activate protein kinase C (PKC)
G-protein a subunit switches itself off
- Normally, the a subunit hydrolyzes its bound GTP to
GDP within seconds - This can also be aided by “GAP-like” proteins in the cell
- GAP=GTPase activating protein
GPCRs and G Protein activation is transient
Once activated, a GPCR can activate many molecules of G protein
A GPCR is deactivated when the signal is no longer available
even if signal remains bound to receptor a GPCR is eventually deactivated and recycled
GPCRs and G proteins have ON & OFF state
Mutations in signaling pathway proteins -> constant “ON” states produce “constitutively active: mutants (e.g: an a-subunit that cannot hydrolyze GTP)
enzyme-coupled receptors
receptors can act as enzymes OR associate with enzymes
receptor tyrosine kinases (RTKs)
- RTKs represent one of the largest class of enzyme-coupled receptors
- They are activated by growth factors (signals), such as FGF (fibroblast growth factor), EGF (epidermal growth factor), etc
- Their cytoplasmic domains function as tyrosine protein kinases
- They regulate growth, proliferation, differentiation and survival of cells
most RTKs activate the small GTPase Ras - how does Ras transmit signal?
~30% of human cancers have activating mutations in Ras
Ras stimulates cell proliferation via the MAP kinase pathway
Ras stimulates the MAPKKK->MAPKK->MAPK (mitogen activated protein kinase) pathway, and thus cell proliferation
some other cancer mutations affect proteins that function in the same pathway as Ras
signaling pathways can be highly interconnected
different signal combinations lead to different cellular outcomes - what does aberrant signaling lead to?
leads to pathological conditions (cancer)
