Flashcards in Exam 3 - Reading CH 15 (Signaling) Deck (40):
What is an extracellular messenger molecule?
1. Usual form of communication.
2. Travel short distance and stimulate cells in close proximity to the origin of the message.
3. Can travel and stimulate cells far from source.
What is autocrine signaling?
1. Cell that is making messenger expresses receptors on its surface that can respond to the message.
2. Stimulates or inhibits themselves.
What is paracrine signaling?
1. Messenger molecules travel only short distances close to cell that is generating the message.
2. Limited because they are a) inherently unstable, b) degraded by enzymes, or c) bind to the extracellular matrix.
What is endocrine signaling?
1. Messenger molecules reach target cells through bloodstream.
2. aka Hormones
3. Typically act on target cells located at distant sites in the body.
What are two additional ways extracellular signals can have an impact on a cell?
1. Neurotransmitters act by opening plasma membrane ion channels.
2. Steroid hormones diffuse though the plasma membrane and bind to intracellular receptors.
What are the two major routes of signal transduction?
1. Second messenger
2. Protein recruitment station
Does each pathway utilize the same proteins?
No, each signaling pathway consists of a series of distinct proteins that operate in sequence.
What does Grb2 and IRS-1 do and what are they?
1. Mediate protein-protein interactions.
2. Modular proteins (many domains to allow dynamic interaction)
Are protein kinases and phosphatases specific or usable by all?
Specific to its substrate.
What are the effects of phosphorylation?
1. Activate or inactivate an enzyme.
2. Increase or decrease protein-protein interactions.
3. Induce a protein to move from one sub cellular compartment to another.
4. Act as a signal that initiates protein degradation.
What are the different kinds of responses initiated by the target protein?
1. Change in gene expression.
2. Alteration of the activity of metabolic enzymes.
3. Reconfiguration of the cytoskeleton.
4. Increase or decreases in cell mobility.
5. Change in ion permeability.
6. Activation of DNA synthesis.
7. Death of the cell.
Where do all signals originate?
At the cell surface.
What is signal transduction?
Process in which information carried by extracellular messenger molecules is translated into changes that occur inside a cell.
What are two ways signals can be stopped or reduced?
1. Extracellular enzymes destroy specific extracellular messengers.
2. Activated receptors are internalized and once inside the cell can be degraded with its ligand leaving the cell with decreased sensitivity to other further stimuli.
What are the different kinds of molecules that function as extracellular carriers of information?
1. Amino acids and amino acid derivatives: Glycine, Glutamate, ACh, Epinephrine (neurotransmitters and hormones).
2. Gases: NO and CO
3. Steroids: derived from cholesterol
4. Eicosanoids: nonpolar molecules derived from arachidonic acid.
5. Polypeptides and proteins.
What do steroid hormones regulate?
1. Sexual differentiation
3. Carbohydrate metabolism
4. Excretion of sodium and potassium ions
What do Eicosanoids regulate?
3. Blood pressure
4. Blood clotting
5. Over the counter drugs: Headaches and inflammation (drugs inhibit eicosanoid synthesis)
What do polypeptides and proteins regulate?
1. Cell division
3. Immune response
4. Cell death/survival
Describe GPCRs and their function.
G protein-coupled receptors
1. Contain seven alpha helices. (7TM = 7 transmembrane receptors)
2. N-term outside of cell, C-term inside.
3. Activates heterotrimeric G proteins.
4. 3 loops outside of the cell that form ligand-binding pocket.
5. 3 loops inside for binding sites for intracellular signaling proteins.
Describe RTKs and their function.
Receptor protein-tyrosine kinases.
1. Ligand binding = receptor dimerization.
2. Activation of receptor's protein-kinase domain (cytoplasmic region).
3. Protein kinases phosphorylate specific tyrosine residues of cytoplasmic substrate proteins.
4. Alters activity, localization, or ability to interact with other proteins within the cell.
Describe Ligand-gated channels and their function.
1. Ligand binding to receptor allows a flow of ions across the membrane.
2. Leads to change in membrane potential affecting voltage-gated channels.
Basis for formation of a nerve impulse.
What is Rhodopsin?
1. Unusually unstable GPCR due to its ligand (retinal group) being permanently bound to the protein.
2. The protein molecule can only exist in a single inactive conformation in absence of a stimulus (in the dark).
What are the steps for a general GPCR mechanism?
1. Inactive form is stabilized by non covalent interactions between specific residues in the TM alpha helices.
2. Ligand binding disturbs interactions causing receptor to assume an active conformation.
3. Increases affinity of receptor for G-protein.
4. Receptor-G protein complex formed.
5. GDP released = G alpha subunit dissociates (conformation change) to effector followed by binding of GTP to G alpha subunit.
6. Activated effector produces second messenger.
7. GTPase activity of G alpha hydrolyzes the bound GTP deactivating G alpha.
8. G alpha reassociates and effector ceases.
9. Receptor is phosphorylated by GRK.
10. Phosphorylated receptor bound by arrestin molecule, which inhibits the ligang-boudn receptor from activating additional G proteins.
Why are G proteins called this way?
They are proteins that bind to guanine nucleotides, either GDP or GTP.
1. Consist of alpha, beta, and gamma.
2. Polypeptide subunits.
3. Exists as heterotrimeric.
4. Held at plasma membrane by lipid chains covalently attached to alpha and gamma subunits.
Where is the guanine nucleotide-binding site present?
On the G alpha subunit.
What happens when G alpha subunit is GTP bound?
1. Loses affinity for G beta-gamma subunit and dissociates from trimeric complex.
2. Activates effector protein.
What do Gs family members activate?
What do Gq family members activate?
- hydrolyzes phosphatidylinositol bisphosphate, producing inositol trisphosphate and diacylglycerol.
What do Gi family members do?
Inhibits adenylyl cyclase.
What do G12/13 family members do?
Known to be activated when their is excessive cell proliferation and malignant transformation.
What does the beta-gamma complex do?
Has a signaling function and can couple to: PLCbeta, K+ and Ca2+ ion channels, and adenylyl cyclase.
What is desensitization and it's steps?
The process that blocks active receptors from turning on additional G proteins.
1. Cytoplasmic domain of activated GPCR is phosphorylated by a specific type of kinase (GRK).
2. Binding of proteins, called arrestins.
What is GRK?
G protein-coupled receptor kinase
1. Small family of serine-threonine protein kinases.
2. Specifically recognize activated GPCRs.
What are arrestins and how do they work?
1. Small family of proteins that bind to GPCRs.
2. Compete for binding with heterotrimeric G proteins.
3. Prevent further activation of additional G proteins.
Describe the steps for Arrestin-mediated internalization of GPCRs.
1 & 2. Arrestin-bound GPCRs are internalized when they are trapped in clathrin-coated pits which bud into the cytoplasm.
3. Localized arrestin-bound GPCRs activate MAPK/ERK transcription factor pathway when in endosome.
4. Alternatively, GPCRs can be delivered to lysosome where it is degraded.
5. Or be dephosphorylated and returned to plasma membrane.
6. Interact with new extracellular ligands (GPCRs)
Where do most bacterial toxins target GPCRs?
G alpha subunit because it is the one that activates the effector. If it is inhibited by toxins, it can't activate it's effector protein.
What does cAMP do?
Stimulates glucose mobilization by activating a protein kinase that adds a phosphate group onto a specific serene residue of the glycogen phosphorylase polypeptide.
- Second messenger
What is a phospholipase?
- Hydrolyze specific ester bonds
What is a phospholipid kinase?