Flashcards in 9.8.16 Lecture Deck (66)
There are up to ___ cells in the body and ___ cell types with specific functions. Cells need to be able to communicate and this occurs through ___.
100 trillion; 1,000; cell signaling
What two things does cell signaling require?
1. A signaling molecule (hormone, NT, etc)
2. Receptor protein
What are the two types of receptor proteins? Describe them.
1. Cell surface receptor protein - binds hydrophilic signals that cannot pass through the membrane
2. Intracellular receptors - binds hydrophobic signals that can pass through the membrane
Different types of signaling are defined by the ___ of the signaling molecule.
What ware the 5 types of signaling as defined by the source of the signaling molecule?
1. Contact-dependent: signaling cell contacts a target cell's receptor via a membrane bound signal.
2. Paracrine - secreted signal affects local cells
3. Autocrine - secreted signal affects local cells of the same type or itself
4. Synaptic - neurotransmitters communicate across a synapse; this is very fast.
5. Endocrine - affects cells far away, travels in the blood; this is very slow
A cell will respond to a signaling molecule only if it has a specific ___ for that molecule.
Receptors must have a high affinity for their signals - why?
The concentration of hormones in the blood is relatively low.
Cells depend on multiple extracellular signals - true or false.
A hormone can have different effects in different types of cells depending on what two things?
The type of receptor present and how the cell is programmed to respond
What is an example of the different effects a hormone can have in different types of cells?
1. Bind to nicotinic receptors on skeletal muscle cells to cause muscle contraction.
2. Bind to M2 receptors of heart muscle cells to decrease the rate and force of contraction.
3. Bind to M3 receptors of salivary gland cells to cause secretion.
Some hydrophobic signals pass through the membrane (passively or via transport) and activate ___. Give an example.
Nuclear receptors; steroid such as cortisol, estradiol, thryoxine, testosterone, vitamine D3, retinoic acid
When steroid hormones bind to their receptors, the receptors typically ___ and then bind to specific ___ to regulate transcription.
Dimerize; DNA sequences
The proteins first created by the binding of hormones are known as ___. They are sometimes ___ that can stimulate gene transcription.
Primary-response proteins; transcription factors
Sometimes the transcription factors created primarily can stimulate transcription of other genes (this is known as a ___ response) or turn off the primary response (this is known as ___).
Delayed secondary; feedback inhibition
The members of the nuclear receptor super family are structurally related and contain what three domains?
1. DNA-binding domains
2. Hormone-binding domains (C-terminal domain)
3. Transcription regulating domains (N-terminal domain)
Inactive nuclear receptors have bound ___ proteins near the ligand (hormone) binding domain. When a hormone binds, ___ changes result in dimerization, the release of these proteins, and the binding of coactivators or corepressors that regulate ___ of specific genes.
Inhibitory; conformation changes; transcription
What are GPCRs?
G-protein-coupled receptors; proteins with 7 transmembrane helices to which signaling molecules bind at the extracellular N-terminus. The cytoplasmic side of the protein interacts with G-proteins.
The G-protein itself is a ___ made up of what subunits? Which subunits are tethered to the membrane? Which subunit binds GDP in the inactive state?
Hetertrimer; alpha, beta, gamma; alpha and gamma; alpha
Describe the general process of activation and inactivation of G-proteins.
1. Signal molecule binds to GPCR.
2. GPCR activates G-protein by stimulating release of GDP, followed by binding of GTP.
3. Activated G-protein (w/GTP) dissociates from the receptor and the alpha subunit dissociates from the beta-gamma subunits. The alpha(GTP)-subunit and/or the beta/gamma-dimmer can activate specific enzymes or ion channels.
4. Hydrolysis of GTP to GDP by alpha-subunit GTPase activity occurs, releasing a phosphate ion. The alpha-subunit and target protein dissociate.
5. The inactive alpha subunit reassembles with the beta-gamma complex to reform an inactive G-protein. This can be reactivated.
What can accelerate inactivation of G-proteins?
Target enzymes or ions channels, or by RGS (regulators of G-protein signaling)
There are many different G-proteins made of various alpha, beta, and gamma subunits. These G-proteins control the activities of various enzymes and ion channels. What are the three main G-proteins and what do they primarily do?
1. Gs - alpha-s mediates activation of adenylyl cyclase
2. Gi - alpha-i mediates inhibition of adenylyl cyclase, beta-gamma activates K+ channels
3. Gq - alpha-q mediates activation of phospholipase C-beta
What happens when a signaling molecule binds to a GPCR that is coupled to Gs?
The G-alpha-s(GTP) subunit activates adenylyl cyclase. This enzyme produces cyclic AMP (cAMP) by removing 2 phosphates from ATP. cAMP is hydrolyzed and inactivated to 5'-AMP by cAMP phosphodiesterase. cAMP affects the cell by activating protein kinase A (PKA).
How does cAMP activate PKA?
cAMP binds to sites on 2 regulatory subunits of PKA and releases 2 activated catalytic subunits which can phosphorylate other proteins.
Where does PKA phosphorylate proteins?
Puts a P from ATP on specific Ser or Thr aa in select proteins, altering their activity.
What is the amino acid sequence that allows PKA to phosphorylate a protein?
Many hormones stimulate cAMP production in their respective target tissues. The consequences of increased cAMP are different in different ___. Why?
Cell types; this is due in part to the fact that their are different proteins present in each cell type available for phosphorylation.
How are phosphorylated proteins dephosphorylated?
How does PKA regulate gene transcription?
Phosphorylation of a TF called CREB in the nucleus
Describe the process of transcription regulation with CREB beginning with activation of a GPCR.
1. Signal molecule activates GPCR
2. Gs alpha-subunit activated
3. Adenylyl cylcase activated
4. cAMP created
5. cAMP activates PKA
6. PKA flows into nucleus via pores
7. PKA activates CREB
8. CREB binds to CRE (cAMP response element) sequence
9. CBP (CREB-binding protein) associates with CREB
10. Transcription occurs