11 receptor-effector coupling Ngu

Question 1

Explain the receptor effect mechanism for lipid soluble ligands

Answer 1

lipid soluble drugs like steroids and hormones directly penetrate cell membranes and bind to receptors in cytoplasm or nucleus

typically has a lag and is long lasting

Question 2

Explain the receptor effect mechanism for Janus Kinase ligands

Answer 2

receptors exist as a dimer which will combine with ligand binding, cytoplasmically the JAK will interact with STAT which can then carry out its effects ie. EPO and IFN drugs

Question 3

Explain the receptor effect mechanism for tyrosine kinase ligands

Answer 3

binding with ligand will dimerize and autophosphorylate the cytoplasmic side. This will then carry out catalytic functions. ie. Insulin, GF

can be downregulated

Question 4

Explain the receptor effect mechanism for ligand gated channels

Answer 4

ligand binding will increase conductance to a specific ion for a very short time
ie. Ach, serotonin, GABA

Question 5

Explain the receptor effect mechanism for G-protein coupled receptors

Answer 5

ligand binding will activate second messenger system and will result in signal amplification

usually have spare receptors

Question 6

what are the five types of G-proteins and their second messengers?

Answer 6

Gs -> activates AC -> increase cAMP
ie. catecholamines, histamine

Gi -> deactivates AC -> decrease cAMP
ie. ACh

Golf -> activates AC -> increase cAMP
ie. odorants

Gq -> activates PLC -> increase DAG/IP3 -> increase cyto Ca++
ie. ACh, catecholamines, histamine

Gt -> activates gPDE -> Decrease cGMP
ie. photons

Question 7

Distinguish between receptor down-regulation and desensitization, putting emphasis on clinical situations in which these phenomena take place.

Answer 7

Down regulation –> protective mechanism where receptors are beta-arrested and endocytosed

desensitization –> beta-arrestin covers interaction site so secondary g messengers can’t act on it

note: desensitization is faster recovering

Question 8

define the cAMP signal cascade

Answer 8

bound g protein will release alpha subunit which will bind to AC which will convert ATP to cAMP which in turn activates PKA which then phosphorylates a variety of molecules

Question 9

define the cGMP signal cascade

Answer 9

similar to cAMP, alpha subunit activates GC which will convert GTP to cGMP which then activates PKG that phosphorylates a variety of molecules

Question 10

define the PLC cascade

Answer 10

PLP C will convert membrane phospholipids into DAG and IP3. DAG activates PKC and IP3 will release internal calcium stores. Calcium will bind to calmodulin and correspondingly create the cellular effects

Question 11

Provide drugs that affect the cAMP, cGMP and PLC cascade

Answer 11

cAMP: theophylline(similar to caffeine) inhibits PDE which breaks down cAMP

cGMP: Sildenafil, bethanechol, bradykinin, histamine will block the gPDE and prolong cGMP

PLC: terazosin, verapamil block PLC and thus decrease Ca++ while norepi increase PLC and thus Ca++

Question 12

Discuss at least two major functions of reversible phosphorylation that are associated with second messenger systems and provide drug examples, and clinical situations associated with each.

Answer 12

signal amplification: a small amount of ligand leading to large effects through messengers ie. nitroglycerin activates PKG and resultant effects

flexible regulation: same second messenger causes different effects in different tissues

ie. epinephrine in heart (incr. inotropy/HR), in bronchioles (dilation)