PHARM: Signal Transduction

Question 1

What is the difference between an effector and a second messenger in a signal transduction cascade?

Answer 1

The effectors are the proteins/enzymes (adenylate cyclase) that catalyze reactions and second messengers are the molecules produced from some of those reactions (cAMP) which can stimulate other biologic activity

Question 2

What is the typical structure of GPCRs?

Answer 2

One protein consisting of 7 transmembrane domains with the N-terminus on the extracellular side and C terminus on the intracellular side. Coupled to alpha, beta, gamma G-proteins

Question 3

Describe the difference in the resting and active state of the GPCRs

Answer 3

At resting state the receptor is coupled to the G-proteins, the alpha subunit of which is bound to GDP. Ligand binding induces a conformational change in the receptor that recruits a G-protein exchange factor that will switch the GDP bound to alpha with GTP. This forms an unstable complex and alpha dissociates from the complex to initiate its own cascade and beta gamma subunits can initiate another cascade

Question 4

Following activation, how does a GPCR return to the resting state?

Answer 4

All alpha G-proteins have intrinsic GTPase activity and the hydrolysis of GTP to GDP causes re association of the complex

Question 5

What are the three main subdivisions of the alpha subunit of GPCRs? What pathway is stimulated by each?

Answer 5

Galpha q activates phospholipase Cbeta which produces IP3 and DAG increasing cytosolic calcium and activating PKC; Galpha s activates adenylate cyclase, producing more cAMP, and activating PKA; Galpha i inhibit adenylate cyclase

Question 6

What type of receptor is the M1 muscarinic receptor?

Answer 6

Galpha q

Question 7

What type of receptor is the M2 muscarinic receptor?

Answer 7

Galpha i/o

Question 8

What type of receptor is the M3 muscarinic receptor? What are the physiologic effects it mediates?

Answer 8

Galpha q; mediates secretion (bronchial, sweat, salivary, gastric acid)

Question 9

What is the major location of the beta 1 adrenergic receptor? What are the relative affinities for EPI and NE?

Answer 9

Myocardium; E=NE

Question 10

What is the major location of the beta 2 adrenergic receptor? What are the relative affinities for EPI and NE?

Answer 10

Vasc. smooth muscle; E (almost none for NE)

Question 11

What is the major location of the beta 3 adrenergic receptor? What are the relative affinities for EPI and NE?

Answer 11

Adipose; NE»E

Question 12

What are arrestins?

Answer 12

Proteins which typically serve to halt the GPCR response by taking the GPCR into an endosome

Question 13

How do tyrosine kinase receptors work?

Answer 13

Exist as monomers in the membrane and when the ligand comes into contact with them monomers, they dimerze and cross-phosphorylate each other, which recruits effector molecules

Question 14

How is nitric oxide produced and how does it act?

Answer 14

Produced by L-arginine by nitric oxide synthase and stimulates guanylate cyclase, which increases cGMP levels and produces vasodilation

Question 15

How is the M3 receptor related to nitric oxide signaling?

Answer 15

Stimulation of the M3 receptor (alpha q) increases calcium and activates endothelial nitric oxide synthase