Exam 2 Lecture 11 Flashcards
What is the main idea behind ligand gated ion channels?
- First messenger binds to the channel (on the outside of the cell)
- Channel opens to allow ions (Na+, Ca2+, K+) to cross
Why are many ligand gated ion channels involved in neuronal signaling?
The neurotransmitter binding to the channel receptor induces ion flow which leads to the postsynaptic signal of depolarization (excitatory cell response) or hyperpolarization (inhibitory cell response)
What are the 2 domains of ligand gated ion channels?
- Extracellular domain that binds the first messenger
2. Transmembrane domain that is the pore in which the ions can flow through
What are some examples of first messengers of ligand gated ion channels?
Serotonin, nicotinic acetylcholine, glutamate, glycine, and GABA
What is the clinical relevance of ligand gated ion channels?
They are thought to be where anaesthetic agents act and are involved in BP regulation and cardiovascular diseases
What is the mechanism of the nicotinic acetylcholine receptor?
- Acetylcholine binding to the extracellular domain triggers a structural change in the transmembrane helices to widen the channel
- The channel opens to allow Na+ ions flow through down the gradient and depolarize the post-synaptic membrane
What is special about the nicotinic acetylcholine receptor?
It is a pentameric receptor
What is the mechanism of receptor tyrosine kinases?
- Ligands induce dimerization of the extra and intracellular domains that will then activate intracellular catalytic activity
- Activated cytoplasmic domains phosphorylate itself on tyrosine (autophosphorylate) to form binding sites specific for a downstream protein
- Sequential phosphorylation of other substrate proteins/downstream signaling proteins
- Signal termination mostly by receptor internalization with ligand dissociation and degradation
What are some examples of receptor tyrosine kinases?
Insulin receptor and growth factor receptors like epidermal GF or platelet-derived GF
How big is the family of receptor tyrosine kinases?
Have numerous families with various extracellular domains that bind the messenger and many are associated with cell growth → dysfunction could result in cancer
Example of the activation of Ras/MAP kinase signal cascade
Growth factor receptor binds the growth factor ligand and initiates the MAP kinase cascade: activated Ras binds and activates MAP3K → MAP2K → MAPK → trigger of the cascade by the phosphorylation of multiple protein substrates
What is the importance of G-protein Ras activation?
There is a molecular switch to activate cell proliferation, migration, transformation, and survival
What happens when there is an oncogenic K-Ras mutation?
- Permanent activation of the Ras enzyme
- Present in the majority of pancreatic ductal adenocarcinoma and other human cancers
- The diagnosis and chemotherapeutic agents are lacking
What is Ras?
Is a membrane bound, monomeric G protein that is critical in cell proliferation, differentiation, adhesion, migration, and apoptosis and is normally activated by growth factors that bind to RTKs or by T cell receptors
What are the 3 Ras genes that are the most common oncogenes in humans and permanent activation can lead to pancreatic cancers?
HRas, KRas, NRas
What is the switch for the activation and inactivation of Ras?
The conformation of the 2 loops differs between the GTP and GDP bound states so the binding of GTP switches from the off to the on state and in the activated GTP bound state, Ras can transiently bind to specific effectors and activate multiple different pathways. Ras can turn itself off by hydrolyzing GTP
What are some examples of Ras effectors?
PLCε, RalGDS, Raf, and PI3K
With receptor tyrosine kinases, what has to happen in order to activate the receptor?
The receptors have to dimerize! If they don’t dimerize, the receptor cannot be activated
In what way do GPCRs have the same structure and in what ways do they structurally differ from one another?
All GPCRs have 7 transmembrane domains (7 places where it crosses the membrane) but the difference between them is where the ligand binds and loops
What are GPCRs and how do they work?
They are a common target for pharmaceuticals and are many hormone and neurotransmitter receptors. They undergo a conformational change upon receiving a signal and they signal through heterotrimeric G proteins (so if there is no G protein, the GPCR won’t do anything)
How are GPCRs different than RTKs?
GPCRs don’t have any enzymatic activity and do not have scaffolding
What are some examples of ligands/first messengers for GPCRs?
Ca2+, odorants, pheromones, small molecules like amino acids, amines, nucleotides, peptides, prostaglandins, and proteins such as TSH, LH, FSH, interleukins, and chemokines
What happens when the G protein is activated?
The alpha, beta, and gamma subunits break up
What is the G protein cycle (trimeric G protein)?
- The release of GDP is slow
- The transient association with an agonist bound GPCR increases GDP release from G𝛼 → GEF activity
- Big amplification occurs in which one agonist bound GPCR can activate 10-100 G proteins
- GTPase activity converts the active/on form (GTP bound) to the inactive/off form (GDP bound) → can be facilitated by RGS proteins
