Module 4 - Receptors and G-protein (PD)

Question 1

Receptors (importance):

Answer 1

The receptor binds to other proteins and chemicals on the outside of the cell and this in turn creates a change in the functioning of the cell.

Proteins also act as drug targets. In order for a drug to exert an effect it needs to be bound to a protein.

Question 2

Types of Receptors

Answer 2

• Ligand-gated Ion Channels
• Enzyme Linked Receptor
• G-protein Coupled Receptor
• Intracellular Receptor

Question 3

Ligand-gated Ion Channels

Answer 3

1. A ligand binds to the receptor, which opens the channel briefly.
2. Ions (hydrophilic) may pass through the cell membrane via the channel.

Question 4

Competitive Antagonist

Answer 4

Binds to the orthosteric site and blocks endogenous agonists.

The dose-response curve will move to the right if a competitive antagonist is attracted to a receptor.

Question 5

Non-Competitive Antagonist

Answer 5

Binds to an allosteric site which reduces the response if a ligand is bound.

The dose-response curve will be reduced greatly in efficacy.

Question 6

G-protein

Answer 6

A protein composed of three subunits, which are Alpha, Beta, and Gamma. (α, β, γ).

Question 7

GDP vs. GTP (G-protein)

Answer 7

GDP is “guanosine diphosphate”, which is attached to Alpha (subunit), when α is together with β and γ, attached to a receptor.

GTP is “guanosine triphosphate” and replaces GDP when a ligand binds to the G-protein receptor. α and β, γ separate from the receptor to cause cellular effects.

Question 8

G-protein Coupled Receptors (steps):

Answer 8

1. A ligand binds to the receptor, and the Alpha subunit switches GDP for GTP.
2. As a result of the switch to GTP (nucleotide guanosine triphosphate), Alpha now separates from the receptor and the other subunits (which consists of Beta and Gamma combined).
3. After the dissociation of Beta and Gamma from Alpha, the Beta and Gamma subunits trigger a response in the cell.
4. Eventually, the GTP is hydrolyzed to GDP, and the ligand will eventually pull away from the receptor.
5. After GTP goes back to becoming GDP, the Alpha, Beta, and Gamma subunits all come back together to form the G-protein, and is attached to the receptor (and the process starts all over again.

Question 9

Enzyme-linked Receptors

Answer 9

1. Ligand binds to the two receptors of the Enzyme-linked receptor to cause conformational change which results in aggregation of both receptors.
2. Once that happens, the tyrosine regions get activated to cause ATP to become ADP.
3. Each tyrosine then picks up a phosphate group, and different inactive intracellular proteins will attach to phosphorylated tyrosine, which will cause conformational change in the attached protein.
4. This will eventually lead to a string of activations which produces cellular responses.

Question 10

Intracellular Receptors

Answer 10

1. The ligand (hydrophobic) will first cross the cell membrane in order to bind with the receptor.
2. The receptor will change its shape once the bind happens, and the receptor-hormone complex is pushed into the nucleus of the cell.
3. The receptor complex will then bind with DNA, leading to synthesis of specific proteins.

Question 11

Types of G-proteins:

Answer 11

• Gs
• Gi
• Gq

Question 12

Adenylyl Cyclase

Answer 12

An enzyme activated by Gs, a stimulative G-protein, which produces cyclic AMP from ATP.

Question 13

Cyclic AMP vs. ATP (G-protein)

Answer 13

A second messenger used for intracellular signal induction. It is synthesized from adenosine triphosphate (ATP) by enzymes (g-proteins) that are attached to metabotropic receptors and become released when the receptor is activated.

Question 14

Gs

Answer 14

A stimulative g-protein which activates an enzyme called adenylyl cyclase. This produces cyclic AMP from ATP, which is important because AMP is an essential second messenger.

Question 15

Gi

Answer 15

An inhibitory G-protein which inhibits adenylyl cyclase to lower levels of cAMP in the cell.

Question 16

Gq

Answer 16

Activates a class of enzymes called Phospholipases C. PLC produces two second messengers, which is the diacylglycerol (DAG), and the inositol (IP3

Question 17

Life of a Receptor:

Answer 17

Cells have the ability to downregulate the receptors, and take them out or replace then when necessary. This is so that the cell can control the amount of stimulation (molecules to bind with receptors).

Question 18

Inverse Agonist

Answer 18

Unlike full and partial agonists, inverse ones will stabilize receptors in their inactive form by eliminating basal activity.

(The curve for this on the dose-response curve goes down, so the response dips).

Question 19

Therapeutic Index

Answer 19

Noted as T1, this measures the relative safety of a drug (the effects in every person is different) for a particular treatment.

It is the ratio of the dose of a drug that produces toxicity in 50% of the population (TD-50) to the dose of a drug that produces effective response in 50% of the population.

( TD-50 / ED-50 )