GPCRs

Question 1

Avidin

Answer 1

This is a protein expressed in avian eggs (egg white), which func;ons to sequester the vitamin bio;n so that bacteria can’t use it and grow inside the egg.

Has a femtomolar K_D for biotin.

Question 2

K_D rate definition

Answer 2

k_off/k_{<span>on</span>}

Question 3

Fractional saturation

Answer 3

Question 4

How fractional saturation curves vary with K_D

Answer 4

Question 5

Standard free energy of binding

Answer 5

Question 6

GPCR Overview

Answer 6

Question 7

GPCRs provide the sensors for. . .

Answer 7

Light, smell, and taste

In the case of light, the GPCRs contain a photosensitive ligand (retinal) that isomerizes when light strikes the retina. In the case of smell, odorant molecules (volatile chemicals) bind to GPCRs in cells in the epithelium lining the nasal cavity, simula;ng nerves that sense smell. In the tongue, taste buds contain specialized cells with GPCRs that bind to molecules in food.

Question 8

“orphan” receptors

Answer 8

GPCRs whose function we do not yet understand, or for which no ligand is yet known

Question 9

metabotropic receptors

Answer 9

In the nervous system, as distinguished from ionotropic receptors, metabotropic receptors signal via metabolic effects such as GTP hydrolysis. (Most are GPCRs)

Effects of GPCR signaling may be longer lasting and affect different signaling pathways than those triggered by activation of ionotropic receptors.

Question 10

Signaling GPCR families

Answer 10

The most studied GPCR family is made up of acetylcholine receptors. The rest are as follow:

Question 11

Sensation GPCR families

Answer 11

Question 12

GPCR Signaling Sketch

Answer 12

Question 13

Structure of a GPCR

Answer 13

The loops are labeled “C” if they are on the cytoplasmic face and “E” if they are on the extracellular (exoplasmic) face. Labeled here are loops C1, C2, and E2; C3, E1, and E3 are not labeled. The small molecule ligand makes contacts with the transmembrane helices as well as the E2 loop

Question 14

GPCR cycle

Answer 14

Question 15

An agonist binds the receptor in a way that. . .

Answer 15

allows it to adopt a conformation that can bind and activate the Gprotein.

Question 16

“On” vs “Off” G protein conformation

Answer 16

Question 17

Adenylyl Cyclase Regulation

Answer 17

Question 18

PKA Signaling

Answer 18

Note that the G protein here is a Gs

Question 19

cAMP

Answer 19

Question 20

Gq PLC Pathway

Answer 20

Question 21

PLC Activity

Answer 21

Question 22

Major Calmodulin Targets

Answer 22

Question 23

Arrestin-mediated GPCR inactivation

Answer 23

Interestingly, arrestin can also recruit proteins from other signaling pathways, and activate them

Question 24

GRK

Answer 24

GPCR-kinase

If a cell encounters a chronically high level of ligand (or perhaps a drug that you might administer) that activates the receptor, this can lead to recognition of the GPCR by GRK. The kinase only binds and phosphorylates the receptor if the receptor is in the ligand bound state. Phosphorylation of the GPCR leads to binding of arrestin.

Question 25

GPCRs are effectively. . .

Answer 25

ligand-dependent GEFs

Question 26

IP₃ vs PIP₃

Answer 26

IP₃ is generated by PLC in response to GPCR/Ga_q signaling

PIP₃ is generated by PI3K in response to RTK signaling

Question 27

Enzyme that produces histamine

Answer 27

L-histidine decarboxylase

Mediates decarboxylation of histidine to form histamine.

Question 28

H1 receptor binding

Answer 28

Causes leaky endothelium on endothelial cells.

Also present in histaminergic neurons in the brain along with H3. Here it controls wakefulness.

Question 29

H2 receptor binding

Answer 29

Induces stomach parietal cell stimulation to release acid.

Question 30

H3 receptor binding

Answer 30

Present in histaminergic neurons in the brain along with H1. Here it controls wakefulness.

Question 31

“We are not the sum of our GPCRs”

Answer 31

There are many other mediators and environmental factors that may control drug efficacy.