G-Protein Coupled Receptor Flashcards
Receptors
-Located mostly in cell membrane
-They receive messages from chemical messengers coming from other cells
-Transmit messages into the cell leading to a cellular effect
-Different receptors respond to different chemical messengers
Neurotransmitters
Chemicals released from nerve endings which travel across nerve synapses to bind with receptors on target cells. They are usually short lived.
Hormones
Chemicals released from cells or glands and which travel some distance to bind to receptors
G Proteins
Guanine nucleotide-binding proteins are a family of proteins that act as molecular switches and are involved in transmitting signals from outside to its interior.
How are GPCRs regulated
Their activity is regulated by factors that control their ability to bind to and hydrolyse guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When GTP is binded they are on and GDP is binded
What enzymes do G proteins belong to
GTPases
GPCR structure
3 intracellular loops
3 extracellular loops
N and C terminals
5 different families of GPCR
Rhodopsin- Serotonin, dopamine
Secretin- Parathyroid hormone
Frizzled/Taster GPCR- cell differentiation and proliferation
Glutamate receptors- Modulation of excitability of synaptic cells
Adhesion class of GPCR- Cell adhesion/cell response and found in immune cells, CNS and reproductive tissue
secondary messengers
cAMP system
Phosphatidylinositol system
cAMP signal
-ligand binds to the GPCR
-conformational changes in the GPCR cause the G-protein complex to disassociate from GPCR
-G alpha protein and GDP are released and GTP binds to Ga protein
-The GTP/Ga binds to adenyl cyclase and activates it which produces cAMP
-The cAMP proteins binds to regulatory protein which stops it from suppressing Kinase A
-Kinase A then phosphorylates other targets
How is CAMP system regulated
-Disassociation of ligand and GPCR does not stop activity
-cAMP phosphodiesterase converts cAMP to AMP which stops kinase activity
-Ga is also a GTPase which converts GTP to GDP which unbinds Ga to adenyl cyclase which stops cAMP production
cAMP stand for
cyclic adenosine monophosphate
IP3 signaling
-ligand binds to GPCR
-Conformational change causes G-protein complex to disassociate and the Ga and GDP are released
-Ga binds to GTP which then bind to phospholipase C which hydrolyses PIP2 releasing DAG and IP3
-IP3 causes the release of cytoplasmic calcium
-DAG activates protein kinase C whose activity is augmented by presence of Ca.
Regulation of IP3
-GTPase activity of Ga halts production of IP3 and DAG
-Removal of CA by calcium ATPase pumps
DAG converted to glycerol or phosphorylated
IP3
inositol-1,4,5-triphosphate
DAG
diacylgylycerol
PIP2
phosphatidyl-4,5-inositol biphosphate
3 categories of GPCR
-agonists
-Antagonists
-Inverse agonists
Agonist
–mimic natural ligand
-Binds reversibly
- similar intermolecular bonds formed as to natural messenger
-Similar structure to NM (natural messenger)
-produce same cellular response
Example Agonist
Clonidine
-anxiety occurs when there is too much norepinephrine in there system
-Drug binds to alpha 2 receptor instead of norepinephrine which tricks the neuron into think there is high norepinephrine in the system which results in a negative feedback response that reduces norepinephrine production.
-less norepinephrine is the system to bind to alpha 1 on post synaptic neuron
-results in reduced nerve signals that increase heart rate and blood pressure which calms the body and so is used to treat symptoms in ADHD
Antagonists`
-Bind to GPCR but does not elicit response
-Reversible binding
-Different induced fit means receptor is not activated
-No reaction takes place on antagonist
-messenger is blocked from binding site
strength of antagonism
-Strength of antagonist binding and antagonist concentration
Inverse agonists
-Blocks activity of endogenous ligand and produces opposite cellular response to natural ligand
Example inverse agonist
Antihistamines like deselex which affects histamine receptors.
-they also affect GABA receptors
Efficacy of agonists, antagonists, etc
agonist- Positive efficacy
Antagonist- zero efficacy
Inverse agonist- negative efficacy
Difference between antagonists and inverse agonists
Antagonists binds to receptor but does not reduce basal activity
Most important factor for GPCR drugs
Compounds that modulate GPCR activity must be able to adopt the specific conformation required by the binding site in order to propagate a signal in the cell to have a desired effect.
Histamine has a very different shape to Claritin
