L13 Basic Concepts in Pharmacology Flashcards
Which receptor type is used for fast transmission and is directly coupled to an ion channel?
Type 1
a.k.a ionotropic receptors
Which receptor type signals via G-protein pathways?
Type 2
a.k.a metabotropic receptors
Which receptor type signals via enzyme-linked cell surface receptors?
Type 3
Which receptor type is located in specialised regions of DNA, and directly promote gene up-regulation (i.e. activate transcription processes)?
Type 4
True or false, Type 1 receptors are associated with fast neurotransmission?
True. Associated with GABA, 5-HT- and ACh
Which receptor type is an ionotropic receptor?
Type 1 (ligand-gated)
Which receptor type is a metabotropic receptor?
Type 2 (G protein-coupled)
Which receptor type is enzyme-linked?
Type 3
Which receptor type is intracellular?
Type 4 (DNA-linked)
What are the key neurotransmitters associated with ionotropic receptors?
ACh, GABA, 5-HT
What kinds of actions are associated with ionotropic receptors?
Breathing and musculoskeletal movements.
Quick actions, autonomic nervous system.
A nicotinic receptor is a classic example of a type __1__ receptor.
It consists of __2__, which will only open when __3__.
Once open, this channel enables __4__.
1) 1
2) 5 transmembrane subunits (2x alpha, 1x beta, 1x gamma, 1x delta)
3) 2 ACh molecules bind (one to each alpha subunit)
4) sodium to flow out, causing depolarisation of the cell.
Which receptor(s) are involved in intracellular signalling?
(Intracellular signalling is when the binding of a ligand activates an enzyme cascade within the cell, producing a cellular response)
Type 2 (G protein)
Type 3 (enzyme-linked)
(Type 4 receptors are generally stimulated by steroids which are lipid soluble. This means the T4 receptors can be located within the cell as the steroid can cross the plasma membrane)
Describe a G protein-coupled receptor
Most consist of a single polypeptide chain of seven transmembrane alpha helices arranged with an extracellular N-terminus and a cytoplasmic carboxy terminus.
(There is a nitrogen on one end that sticks out of the cell and a carbon on the other end that sticks into the cell, with seven loops weaving in and out of the membrane)
In a G protein-coupled receptor (type 2), which loop is coupled to a G protein?
The 3rd loop
In a G protein-coupled receptor (type 2), where does the ligand bind?
There is a binding site in the alpha helices which are embedded in the membrane.
What are the 3 subunits the make up a G protein?
Alpha, beta, and gamma.
Which of the G protein subunits are associated with the plasma membrane?
Beta and gamma form a complex that remains bound to the intracellular surface of the plasma membrane,
What are the 3 stages of G protein activation?
1) Binding of a ligand to the type 2 receptor - allows a conformational change in the alpha, beta and gamma complex, allowing the alpha to exchange the GDP for a GTP and this causes the alpha to dissociate from the beta and gamma subunits.
2) The alpha coupled to the GTP then associates with specific allosteric target enzyme (such as an adenylate cyclase).
3) The alpha hydrolyses GTP into GDP. This inactivates the enzymatic ability of the alpha subunit whilst allowing the activation of the target enzyme. The inactive alpha subunit then re-associates with the beta and gamma complex
G-protein mechanisms can act as a signal amplifier - a single activated receptor can activate several G proteins.
G proteins target a whole range of membrane proteins, most well known include:
- __1__, to produce intracellular cAMP
- __2__, to produce intracellular cGMP
- Phospholipase C/__3__ system
- The regulators of __4__
1) Adenylate cyclase
2) Guanylate cyclase
3) inositol phosphate
4) ion channels
Activated adenylate cyclase converts __1__ into __2__.
1) ATP
2) cAMP
cAMP functions as a __1__ and is inactivated by __2__, which hydrolyses it into __3__. Drugs such as __4__ can prevent the deactivation of cAMP.
1) second messenger
2) phosphodiesterase
3) 5’-AMP
4) caffeine
What is the main target of cAMP?
Inactive protein kinases - it activates them.
cAMP plays a part in lots of processes - e.g. increased activity of voltage-sensitive Ca channels in the __1__ and inactivation of myosin light chain kinase in __2__.
1) heart
2) smooth muscle
Adrenaline causes liver cells to reduce glycogen synthesis and increase glycolysis. What receptor is associated with this process?
Type 2 (G protein-coupled)
Type 2 (G protein-coupled) receptors commonly utilise the adenylate cyclase and cAMP system, but there are others.
In the phosphoinositide system, the G protein activates __1__, which splits __2__ (PIP) into __3__ (DAG) and __4__ (InsP).
Both DAG and InsP act as __5__, each giving different results.
1) phospholipase C
2) phosphoinositide diphosphate
3) diacylglycerol
4) inositol triphosphate
5) second messengers
In the phosphoinositide system, DAG results in __1__, while InsP results in __2__.
1) protein kinase C activation
2) Ca2+ release from intracellular stores
How does inositol triphosphate cause calcium to be released from intracellular stores?
InsP3 binds to endoplasmic receptors and opens endoplasmic Ca2+ channels. This allows the release of Ca2+ into the cytosol where the Ca2+ can interact with a whole range of targets.
Diacylglycerol activates protein kinase C. What events are associated with PKC?
- Muscle contraction
- Inflammatory response
- Increased neurotransmitter release
In addition to the cAMP, cGMP, and phosphoinositide systems, how else can G proteins act?
G-proteins can also directly activate ion channels
Interaction of ACh and muscarinic receptors opens potassium channels via a G-protein pathway.
Describe the guanylyl cyclase G protein cascade.
Extracellular domain binds the ligand.
On binding ligand, intracellular domain (the guanylyl cyclase) becomes activated and produces cyclic GMP.
Cyclic GMP binds to cyclic GMP-dependent protein kinase (G-kinase)
G-kinase then phosphorylates downstream proteins on either threonine or serine residues.
In this system cGMP acts as a secondary messenger.
What is an example of a receptor that uses the guanylyl cyclase cascade?
The receptor for atrial natriuretic peptide.
If activation of a type 2 (G protein-coupled) receptor results in contraction, what was most likely activated by the G protein?
Phospholipase C - produces InsP3 (promotes Ca2+ release) or DAG which both activate contractile proteins.
This is the phosphoinositide system.
Which G protein pathways can affect ion channels?
All of them. cAMP, cGMP, phospholipase C can all affect ion channels. G proteins can also do this directly, without the need of messengers.
What are the four variants of Type 3 (enzyme-linked) receptor?
1) Receptor tyrosine kinases
2) Receptor linked tyrosine kinases
3) Receptor tyrosine phosphatases
4) Receptor serine/threonine kinases.
What is the major difference in how a type 2 and type 3 receptor work?
T2 have an intermediary (g-protein) but T3 is direct
Where are Type 4 receptors found?
In the nucleus, wrapped around DNA.
How do Type 4 receptors respond when a molecule binds?
Typically form target for steroid hormones.
Steroids are lipid soluble, bind to the receptor, the receptor unfolds allowing the receptor to bind to specific DNA sequences (known as hormone responsive elements) and so promote increased RNA polymerase activity and gene transcription.
In this system the DNA receptors are very specific to the hormone.
What type of T4 receptor is associated with growth factors and insulin?
Receptor tyrosine kinases
What type of T4 receptor is associated with integrins?
Receptor-linked tyrosine kinases
What is the function of receptor tyrosine phosphatases?
Hydrolyse target proteins, deactivating them
What is the function of receptor serine/threonine kinases?
Phosphorylate proteins
Adapter proteins are associated with receptor tyrosine kinases. True or false?
True.
