Receptor signalling

Question 1

what are ligands?

Answer 1

chemicals that act on specific receptors to evoke a particular response

Question 2

define specificity…

Answer 2

where certain ligands (or drugs) bind to certain receptors-this is reciprocal and receptors only recognise certain types of drugs

Question 3

what are agonists?

Answer 3

-ligands that when bound to receptors it elicits an observable response-it may be endogenous (glutamate) or exogenous (drugs like NDMA)

Question 4

what are antagonists?

Answer 4

pharmacological antagonists that compete with agonists to alter the interaction between agonists and their receptors

Question 5

how many families of receptors are there?

Answer 5

4

Question 6

why can’t most endogenous ligands cross the membrane?

Answer 6

-they are hydrophilic and so can’t cross the cell membrane and act on plasma membrane receptors

Question 7

what are nuclear receptors?

Answer 7

-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

Question 8

how do receptors act as transducers?

Answer 8

-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

Question 9

what does a ligand induce in the GPCR?

Answer 9

in the GPCR,the ligand induces the release of intracellular second messengers which act on various signalling pathways

Question 10

what are the principles of G-protein coupled receptors?

Answer 10

-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

Question 11

what do the G-proteins bind to?

Answer 11

guanine nucleotides:GDP (guanine diphosphate) and GTP (guanine triphosphate)

Question 12

how many subunits do G-proteins have?

Answer 12

3-α, β and γ
-the a subunit binds to GDP,GTP and has GTPase activity

Question 13

what happens in G-protein signalling 1?

Answer 13

-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

Question 14

what happens in the G-protein signalling 2?

Answer 14

-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

Question 15

what are the different multiple ligand intracellular targets that Ga subunits act on?

Answer 15

-Gs stimulate Protein Kinase A (PKA)/cAMP signalling
-Gi inhibit PKA/cAMP signalling
-Gq stimulate Phospholipase C/DAG signalling pathways

Question 16

what do second messenger systems do?

Answer 16

they regulate multiple intracellular signalling pathways

Question 17

state a target of the Gβ/γ subunits..

Answer 17

ion channels

Question 18

how many GPCRS are there?

Answer 18

-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

Question 19

what is adenylate cyclase?

Answer 19

-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

Question 20

what does cAMP do?

Answer 20

-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

Question 21

what do drugs that inhibit PDEs do?

Answer 21

-they keep cAMP levels elevated e.g theophylline used therapeutically to maintain elevated cAMP and relax bronchial smooth muscles in the treatment of asthma

Question 22

what does PKA do?

Answer 22

regulates cellular activity by phosphorylating its target proteins with many functions including regulation of glycogen, sugar and lipid metabolism

Question 23

what does the consequences of GPCR activation and altered cAMP signalling depend on?

Answer 23

-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