Receptor signalling Flashcards
what are ligands?
chemicals that act on specific receptors to evoke a particular response
define specificity…
where certain ligands (or drugs) bind to certain receptors-this is reciprocal and receptors only recognise certain types of drugs
what are agonists?
-ligands that when bound to receptors it elicits an observable response-it may be endogenous (glutamate) or exogenous (drugs like NDMA)
what are antagonists?
pharmacological antagonists that compete with agonists to alter the interaction between agonists and their receptors
how many families of receptors are there?
4
why can’t most endogenous ligands cross the membrane?
-they are hydrophilic and so can’t cross the cell membrane and act on plasma membrane receptors
what are nuclear receptors?
-a family of ligand-regulated transcription factors that are activated by steroid hormones such as oestrogen and other lipid soluble signals increase retinoid acid,oxysterols and thyroid hormones
how do receptors act as transducers?
-they receive a signal in one form (ligand binding) and transform this to a different type of signal known as signal transduction e.g the ligand may directly open an ion channel which has a rapid effect e.g at synapses
what does a ligand induce in the GPCR?
in the GPCR,the ligand induces the release of intracellular second messengers which act on various signalling pathways
what are the principles of G-protein coupled receptors?
-they are the largest cell surface receptors
-there is a wide range of ligands,inc neurotransmitters with multiple intracellular targets and diverse cellular effects
-all have seven transmembrane (7TM) domains
-extracellular domain binds to the ligand e.g glutamate
-intracellular domains are coupled to the G-protein
what do the G-proteins bind to?
guanine nucleotides:GDP (guanine diphosphate) and GTP (guanine triphosphate)
how many subunits do G-proteins have?
3-α, β and γ
-the a subunit binds to GDP,GTP and has GTPase activity
what happens in G-protein signalling 1?
-it is the resting state where the α subunit binds to GDP
-when a ligand binds, the receptor is activated and this causes a conformational change resulting in the release of GDP in exchange for GTP
-the activated G-protein dissociates into the a subunit and the β/γ complex -both are biologically active
what happens in the G-protein signalling 2?
-the G-protein subunits diffuse along the membrane surface to activate or inhibit target proteins which are often enzymes that generate second messengers
-the Ga protein has GTPase activity and this hydrolyses the bound GTP to GDP,which then inactivates the Gα protein
-this causes the subunits to recombine to reform the Gα−β−γ complex to restore the G-protein to its inactive state ready to be activated again,in this way the Gα subunit functions as a molecular switch -when it is bound to GTP it is ON and when bound to GDP it is off
what are the different multiple ligand intracellular targets that Ga subunits act on?
-Gs stimulate Protein Kinase A (PKA)/cAMP signalling
-Gi inhibit PKA/cAMP signalling
-Gq stimulate Phospholipase C/DAG signalling pathways
what do second messenger systems do?
they regulate multiple intracellular signalling pathways
state a target of the Gβ/γ subunits..
ion channels
how many GPCRS are there?
-over 1000,they are activated by many ligands which act on multiple subtypes of GPCR with multiple effects e.g α and β adrenergic receptors which are respectively coupled to Gi and Gs-GPCRs and regulate many different cellular systems which is highly cell dependent
what is adenylate cyclase?
-AC is a key target of G proteins
-AC has a basal activity in cells so can be increased or decreased
-it converts ATP to the second messenger cyclic AMP
what does cAMP do?
-activates many intracellular processes
-regulates protein kinase A
-the cAMP activity is controlled by the enzyme phosphodiesterase (PDE) which converts camp to -5’AMP
-GPCR coupled to Gs stimulate AC to increase cAMP
-GPCR coupled to Gi inhibit AC cAMP
what do drugs that inhibit PDEs do?
-they keep cAMP levels elevated e.g theophylline used therapeutically to maintain elevated cAMP and relax bronchial smooth muscles in the treatment of asthma
what does PKA do?
regulates cellular activity by phosphorylating its target proteins with many functions including regulation of glycogen, sugar and lipid metabolism
what does the consequences of GPCR activation and altered cAMP signalling depend on?
-the signalling varies from one cell to another depending on the receptor subtype e.g B-adrenore ceptors are coupled to Gs which stimulates cAMP signalling whereas a-adrenoreceptors are coupled to Gi in which the signalling decreases cAMP signalling
what is phospholipase C (PLC) ?
an enzyme that leaves the membrane phospholipid phosphatidylinositol diphosphate (PIP3) to yield inositol trisphosphate (IP3) and diacylglycerol (DAG) both of which are second messengers.
what does IP3 do?
releases Ca2+ from intracellular stores in the endoplasmic reticulum
state a key calcium target…
-calcium/calmodulin dependent protein kinase (CAMK)
what does DAG do?
-exerts its effects via activation of protein kinase C (PKC) which phosphorylates target proteins that vary between different kinds of cells
what are the effects of PKC?
-the effects of PKC are cell type specific and some effects are receptor desensitisation,transcription,immune responses, cell growth, learning and memory
what ion channels can G-proteins regulate?
-they can activate K+ channels
-they can inhibit voltage-gated calcium channels
how do β/γ subunits of G-proteins regulate ion channels and neurotransmission?
-β/γ subunits interact with ion channels and regulate neurotransmission by:
-activating GIRK channels (K+ channels),leads to hyperpolarization and inhibits synaptic neurotransmission
-inhibiting Ca2+ channels,inhibtis synaptic transmission
what do GPCRs do?
-regulate innumerable cell functions throughout the body because they are expressed in all cells and tissues of the body
-they are the main targets for therapeutic drugs
blurt table for GPCR drugs that act via cAMP
