Signaling receptors

Question 1

GPCR structure

Answer 1

7 TM domains into barrel-like pore where ligand binds
Amino terminus into ECF
Carboxyl terminus into cytoplasm
Loops that extend into cytoplasm (i-loops) confer special G protein binding

Question 2

G proteins

Answer 2

Alpha unit that binds GDP/GTP
Beta/Gamma unit that act as one
Ligand binding to the receptors gives it the ability to make the reaction that exchanges GDP for GTP on the alpha unit more favorable
Since nucleotide exchange is the rate-limiting step of the cascade, this allows for the activation of the cellular pathway

Question 3

Mechanism

Answer 3

Alpha binds GTP, dissociates from beta-gamma so they can both go do things.
Alpha is GTPase, turns its gtp-gdp with help of gap and is recycled to mem.

Question 4

Beta-adrenergic receptors (heart)

Answer 4

Norepinephrine binds the receptor, causing GDP/GTP exchange and the activation of the Gs alpha unit which binds to adenylyl cyclase (AC) to activate it.
AC creates cAMP, a second messenger, increasing levels in the cell, which in turn activate protein kinase A (PKA).
PKA phosphorylates Ca channels, leading to influx of Ca. These steps lead to contraction of cardiac muscle

Question 5

M2 muscarinic cholingergic receptors (sympathetic input)

Answer 5

acetylcholine binds the receptor, activating the Gs protein with GTP which binds AC and increases cAMP leading to increased heart rate.

Question 6

Desensitization

Answer 6

GRK phosphorylates the cytoplasmic loops of the G protein coupled receptor. This results in its
inability to interact with G proteins. Also, these phosphorylated residues recruit a protein called beta
arrestin.
beta arrestin further prevents G proteins from associating
This also acts as an adaptor for endocytic machinery… internalization of the entire receptor.

Question 7

Atropine

Answer 7

Ach antagonist. prevents action of Gi with GTP, stops para-sym so Gs wins and heart contracts.

Question 8

PDE inhibs

Answer 8

Caffeine… target PDE which is constitutively active and degrades cAMP so PKA can’t be activated and signal is terminated.
Allows extended signaling.
So you allow PKA activation… get heart rate contractin etc.!

Question 9

Metoprolol

Answer 9

B-adrenergic receptor antagonist

Prevents cAMP increase b/c of Norepi, so decreased heart rate