GCPRs Flashcards
What is an agonist?
A substance that interacts with a receptor such as to activate it
GCPRs & RTKs have to be activated by agonist molecules
What is a treatment for asthma?
Inhalation of an adrenoceptor agonist (e.g. Salbutamol)
Activates adrenoceptors in the lung smooth-muscle
Causing the lungs to relax (bronchodilation)
What happens when beta-adrenergic receptors couple to Gs subunits?
Activates adenylyl cyclase, stimulating it to produce cAMP which activates protein kinase A (PKA)
What happens when ACh muscarinic M1 / alpha-adrenergic receptors couple to Gq subunits ?
- Stimulate phospholipase C which breaks down phospholipid PIP2 —> DAG + InsP3
- DAG can then activate protein kinase C (PKC) and InsP3 can release Ca2+ from intracellular stores
What does the coupling of opioid / acetylcholine muscarinic M2 receptors to Gi/o subunits do?
Can down-regulate adenylyl cyclase / affect ion channel activity
What does Gs do?
Stimulates adenylyl cyclase
What does Gq do?
- Activates phospholipase C which breaks down cell phospholipid PIP2 —> DAG (diacyglycerol) and inositol ((1,4,5)-triphosphate - InsP3 / IP3)
- InsP3 releases Ca2+ from intracellular stores which activates other processes
What does Gi/o do?
Can inhibit adenylyl cyclase and interact with a variety of targets (inc. ion channels)
What does adenylyl cyclase do?
Stimulated by certain GCPRs to produce cAMP (cyclic 3’,’-adenosine monophosphate)
Increased [cAMP] in the cell activates cAMP-dependent protein kinase A (PKA) which causes phosphorylation of other proteins (e.g. ion channels)
What are the immediate symptoms of anaphylactic shock? (3)
Laryngeal oedema (swelling of the larynx)
Bronchospasm (constriction of the airways)
Hypertension (loss of blood pressure)
What are the advantages of using inhalers in the treatment of asthma?
By inhaling the drug, it allows it to be specifically applied to where it is needed (the lungs) and by the time it reaches other targets where the effect is not wanted (e.g. the heart), it has become diluted
What are the 3 different sub-units of the heterotrimeric G-protein?
Alpha
Beta
Gamma
What are GPCRs?
G-protein coupled receptors
Proteins embedded in the cell membrane that transmit external signals into the cell
They have a diverse range of physiological functions
What are GCPRs also known as?
7TM receptors
What are G-proteins?
Guanine nucleotide-binding proteins
Bind GTP (guanosine triphosphate) and GDP (guanosine diphosphate)
What are examples of functions of GCPRs?
Used to:
Detect photons in the eyes & odours in the nose
Speed up / slow down the heart
Regulate blood pressure & secretion of stomach acid
What drug (which targets GCPRs) is used to treat migraines?
Sumatriptan (Imigran)
What drug (which targets GCPRs) is an antihistamine?
Cetirizine (Zirtek)
What drug (which targets GCPRs) is used to treat asthma?
Salbutamol (Ventolin)
What drug (which targets GCPRs) is used to treat hypertension (high BP)
Atenolol (Tenormin)
What are effectors?
Cell enzymes / ion channels that are targets for G-protein modulation
How have pharmacologists tried to minimise unwanted side effects of inhalers?
By using drugs designed to interact b2 adrenoceptor in the lung smooth-muscle instead of the b1 adrenoceptor which causes the most cardiac effects
Describe the structure of the G-protein in its resting state
All 3 G-protein subunits (alpha, beta, gamma) assembled together
GDP molecule is bound to the alpha subunit
Describe the process of receptor G-protein coupling
- With no agonist bound to the receptor, both the receptor & G-protein are inactive
- Agonist binding to receptor causing it to undergo a conformational change
- This causes a conformational change in the G-protein so that the alpha subunit releases the bound GDP molecule
- GDP molecule replaced by GTP
- GTP binding causes alpha subunit to dissociate from the beta & gamma subunits and bind to the effector - bringing about a physiological change by either activating / inhibiting the effector
- Cycle ends when the alpha subunit breaks down GTP —> GDP + Pi
- Alpha subunit leaves the effector and rejoin the beta & gamma subunits
What do GPCRs do?
Mediate the majority of cellular responses to external stimuli
Mediate most cellular responses to hormones & NTs
Responsible for vision, olfaction & taste
What are the (2) effectors for GPCRs?
Enzymes & ion channels
What does the Opioid / M2 Muscarinic receptor do?
Interacts with K+ channels
Inhibits (membrane-bound) adenylyl cyclase (decreasing [cAMP])
(Can) inhibit Ca2+ channels
What does the beta-adrenergic GPCR do?
Stimulates adenylyl cyclase (inc [cAMP])
Activates PKA (protein kinase A)
- this has additional impacts (e.g. activating Ca2+ channels)
What does the M1 muscarinic / a1-adrenergic GPCR do?
Activates phospholipase C (enzyme which breaks down the membrane into diacyglycerol (DAG) + inositol (InsP3 / 1,4,5-triphosphate)
- InsP3 promotes intracellular release of Ca2+
- DAG activates PKC
What is the effect of vibrio cholerae on GPCRs?
Cholera toxin is secreted by invading bacteria and so infiltrates cells
The toxin catalyses the ADP-ribosylation of some subtypes of G-protein alpha subunits
The subunit is therefore unable to hydrolyse GTP - GDP, resulting in the G-protein being permanently ‘switched on’
Elevated levels of cAMP produce the symptoms of excessive loss of fluid from the GI (causing diarrhoea)
How does adrenaline in epipens reverse the effect of allergies?
Allergies cause swelling of the larynx, dec BP & constriction of the smooth muscle in the airways leads to difficulty breathing
Adrenaline raises BP and relaxes smooth muscle
Describe the action of Salbutamol
Artificial adrenaline - activates adrenoceptors
More selective for adrenoceptors in the lungs than the heart - so the heart doesn’t race
What drugs can be used to reverse the constriction of the smooth muscle in airways due to asthma / allergies?
Ventolin
Salbutamol (artificial adrenaline)
Adrenaline relaxes smooth muscle in airways & raises BP
What are 2 key examples of G-protein receptor pharmacology?
Adrenaline in the treatment of anaphylactic shock
Adrenaline-like agonists in the treatment of asthma
Gs, Gi/o and Gq are all types of alpha-subunit. What are their different effects?
Gs - stimulates adenylyl cyclase (inc [cAMP])
Gi/o - can inhibit adenylyl cyclase and interact with a variety of targets (including ion channels)
Gq - can activate the enzyme phospholipase C
What happens when Gq activates phospholipase C?
- Activated phospholipase C breaks down (cell phospholipid) PIP2 —> DAG (diacyglycerol) + InsP3 ((1,4,5)-triphosphate)
- DAG activates PKC (protein kinase C)
- InsP3 releases Ca2+ from intracellular stores
G-proteins are usually referred to by the subtype of alpha subunit that they contain. What are the different types of alpha subunit?
Gs
Gi/o
Gq
Which receptors couple to Gi/o subunits?
Opioid & ACh muscarinic M2 receptors
Which receptors couple to Gq subunits?
ACh muscarinic M1
alpha-adrenergic
What type of receptor couples to Gs subunits?
Beta-adrenergic
What are the immediate symptoms of anaphylactic shock?
Laryngeal oedema (swelling of the larynx)
Bronchospasm (constriction of the airways)
Hypertension (loss of blood pressure)
What is used to reverse the immediate symptoms of anaphylactic shock?
Injection of adrenaline (epinephrine)
What is asthma and what is a treatment for it?
Asthma is constriction of the airways caused by an adverse immune reaction triggered in the lungs
Treatment is the inhalation of an adrenoceptor agonist (e.g. Salbutamol), which activates adrenoceptors in the lung smooth-muscle, causing them to relax (bronchodilation)
What does the stimulation of adenylyl cyclase do?
Adenylyl cyclase is stimulated by certain GPCRs to produce cAMP (cyclic 3’,5’-adenosine monophosphate)
Increased [cAMP] in the cell activates cAMP-dependent protein kinase A which causes the phosphorylation of other proteins (e.g. ion channels)
What is the G-protein associated with GPCRs?
Heterotrimeric G-protein
Give 4 examples of drugs which target GPCRs and what they do
- Sumatriptan (Imigran) - for migraines
- Cetirizine (Zirtek) - antihistamine
- Salbutamol (Ventolin) - for asthma
- Atenolol (Tenormin) - for hypertension (high BP)
