PHARMACOLOGY 1 Flashcards
what is a type 1 receptor?
fast neurotransmission - directly coupled to an ion channel – ionotropic receptors
what is a type 2 receptor?
signal via G-protein pathways – metabotropic receptors
what is a type 3 receptor?
signal via enzyme-linked cell surface receptors
what is a type 4 receptor?
located in specialized regions of DNA, activation directly promotes gene up-regulation
what does the nicotinic Ach receptor consist of?
5 memb spanning subunits - 2 alpha, beta, gamma, delta
how does the nicotinic Ach receptor open?
2 Ach molecules bind to the 2 units - this opens the ligand-gated Na ion channel and depolarises the cell.
what is intracellular signalling?
describes the way the binding of a ligand with a receptor activates an enzyme cascade, ultimately inducing a cellular response.
what is the function of receptors?
provide a means of selectively transmitting extracellular signals across the cell membrane, enabling cells to respond to the stimuli.
what do cellular responses include?
opening of ion channels, increased secretion of other signalling molecules, cell motility and modifications of the cell cycle
what are the 2 types of intracellular signalling?
G-protein pathway - Type 2 receptors
enzyme-linked cell surface receptor pathway - Type 3 receptors
what do type 2 receptors consist of?
most consist of a single polypeptide chain forming seven transmembrane helices arranged with an extracellular N-terminus and a cytoplasmic carboxy terminus
where does the ligand bind in type 2 receptors?
binds to a binding site in the helices embedded in the memb
what part of the receptor couples to a G-protein?
the 3rd loop
what are G-proteins?
Exist as highly mobile proteins in the membrane
what do G-proteins consist of?
consist of 3 subunits, alpha, beta and gamma
what does the alpha subunit function as?
as a GTPase, converting GTP to GDP
what do the beta and gamma subunits do?
and subunits form a complex, are very hydrophobic and stay closely associated with the memb
what happens when the protein is inactivated?
the alpha, beta and gamma subunits form a complex in which GDP is bound to an alpha subunit
what is the 1st stage of G protein activation?
Binding of a ligand to the 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 and subunits.
what is the 2nd stage of G protein activation?
The coupled to the GTP then associates with specific allosteric target enzyme such as an adenylate cyclase.
what is the 3rd stage of G protein activation?
The 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
what can the G protein mechanism act as?
as a signal amplifier - a single activated receptor can activate several G proteins.
what are the targets for G proteins?
Adenylate cyclase
Guanylate cyclase
Phospholipase C/inositol phosphate system
The regulators of ion channels
what does adenyl cyclase produce?
intracellular cAMP
what does guanyl cyclase produce?
intracellular cGMP
what does activated adenyl cyclase do?
converts ATP into cAMP
what is cAMP?
cyclic 3’,5’-adenosine monophosphate, cAMP functions as a secondary messenger and is inactivated by hydrolysis into 5’-AMP.
how does cAMP act?
targets inactive protein kinases, activating them
what do the activated protein kinases do?
use ATP as a source of phosphate groups and phosphorylate downstream enzymes thus activating them.
give an example of cAMP’s role
cAMP role in beta adrenoceptor activated breakdown of glycogen
how is cAMP inactivated?
by phosphodiesterase. Inactivation can be inhibited by drugs such as caffeine.
what is the phosphoinositide system?
based on memb phospholipid phosphoinositide (4,5) diphosphate (PIP2)
what is the role of PIP2?
acts as a substrate for a membrane-bound enzyme phospholipase C (PLC) which spits PIP2 into diacylglycerol (DAG) and inositol (1,4,5) triphosphate InsP3.
what are the secondary messengers in the phosphoinositide system?
DAG and InsP3
what do DAG and InsP3 do?
DAG results in protein kinase C activation and InsP3 promotes Ca2+ release from intracellular stores
how does InsP3 work?
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
what is Ca important in?
Muscle contraction
Control of secretion from exocrine glands (ie., the muscarinic ACh receptor)
Hormone release
what does DAG activate?
activates PKC which is a serine/threonine kinase and acts by phosphorylating downstream target enzymes.
what things are associated with the PKC being activated?
Muscle contraction
Inflammatory response
Increased neurotransmitter release
what effect do G-proteins have on ion channels?
directly activate ion channels, ie., interaction of ACh and muscarinic receptors opens potassium channels via a G-protein pathway
how does the guanyl cyclase receptor work?
Extracellular domain binds the ligand.
On binding ligand, intracellular domain (the guanylyl cyclase) becomes activated and produces cyclic GMP.
what does cyclic GMP do?
binds to cyclic GMP-dependent protein kinase (G-kinase)
what does G-kinase do?
phosphorylates downstream proteins on either threonine or serine residues
what is the secondary messenger in the guanyl cyclase receptor system?
cyclic GMP
give an example of guanylyl cyclase receptor
the receptor for atrial natriuretic peptide.
what are type 3 receptors?
Trans-Memb proteins possessing an extracellular ligand binding domain and a cytoplasmic domains that have an intrinsic enzymatic activity.
what are the 4 kinds of type 3 receptors?
tyrosine kinases
Receptor linked tyrosine kinases
tyrosine phosphatases
serine/threonine kinases
