ß2-ADRENERGIC RECEPTOR

Brittaney Rigby

WHAT IS A β2-ADRENERGIC RECEPTOR (β2-AR)?

•ß2-AR is a type of G protein-coupled Receptor.

•G-PCRs contain 7 transmembrane alpha helices.

2β-AR CYCLE SUMMARY

1. Ligand Specificity

2. Ligand Binding

3. Message Amplification

4. Message is Turned Off

5. Receptor is Recycled

1. LIGAND SPECIFICITY

• Epinephrine (adrenaline)• Norepinephrine (noradrenaline)• Dopamine• Albuterol (ß2-AR agonist)

2. LIGAND BINDING

A. Epinephrine binds to ß2-AR.B. This causes a conformational change in the receptor that

induces Gα to release GDP and then bind to GTP.A. Gsα is specific to ß2-AR

C. This causes the dissociation of Ga from Gßy and the activation of both Ga and Gßy.

D. Ga binds to Adenylate Cyclase and stimulates the production of cAMP.

2. LIGAND BINDING

2. LIGAND BINDING

3. MESSAGE AMPLIFICATION

• Adenylate Cyclase cAMP production from ATP is increased.• Four cAMP molecules bind to the R2C2 tetramer.• PKA is activated. This leads to:

1. Inhibition of glycogen synthesis2. Activation of glycogen degradation3. Activation of glucose synthesis

• Net Result = Glucose export

3. MESSAGE AMPLIFICATION

4. MESSAGE IS TURNED OFF

• ß-adrenergic receptor kinase (ßARK) is attracted to the membrane by GßY and binds to it.• ßARK phosphorylates ß2-AR at the C-terminus (Ser and Thr).• PKA can also phosphorylate the ß2 receptor.

• ß-Arrestin binds to the phosphorylated C-terminal domain of the protein.• An endocytic vesicle forms around the receptor via

membrane invagination.

4. MESSAGE IS TURNED OFF

WHAT ABOUT GΑ SIGNAL TERMINATION?• A GAP binds to Gα-GTP

complex.• This stimulates Gα to

hydrolyze GTP to GDP.• The GAP leaves

• Gαßy reassociates with a GPCR

5. RECEPTOR IS RECYCLED (OR NOT)The receptor is dephosphorylated and sent back to the plasma membrane (or sent to the lysosome).

RECALL: THE B2-AR SHARES THE SAME EXACT PATHWAY AS THE GLUCAGON RECEPTOR

WHY DOES THE Β2-ADRENERGIC RECEPTOR HAVE A DIFFERENT EFFECT THAN THE GLUCAGON RECEPTOR EVEN THOUGH THEY

SHARE THE SAME PATHWAY?

ANSWER

• Different tissues respond to different hormones based on receptor type, receptor location, and what is targeted.• Skeletal muscles have on epinephrine receptors, but they don’t

have glucagon receptors.• The liver, however, has both epinephrine and glucagon

receptors.• Different enzymes are available for the same kinase• Glycogen breaks down into lactate in muscles and lactate is

released into the blood.• Glycogen breaks down into glucose in the liver and glucose is

released into the blood.

REFERENCES

• Farzam, K. (2019, November 19). Adrenergic Drugs. Retrieved February 5, 2020, from https://www.ncbi.nlm.nih.gov/books/NBK534230/

• Klabunde, R. (n.d.). Beta-Adrenoceptor Agonists (β-agonists). Retrieved February 5, 2020, from https://www.cvpharmacology.com/cardiostimulatory/beta-agonist

• Miesfeld, R. L. and M. M. McEvoy. 2017. Cell signaling systems. B. Twitchell, editor. Biochemistry. New York: W. W. Norton and Company, Inc. 385-396.

• Mowshowitz, D. (n.d.). C2006/F2402 '11 OUTLINE OF LECTURE #16. Retrieved February 6, 2020, from http://www.columbia.edu/cu/biology/courses/c2006/lectures11/lect16.11.html

• PDB101: Molecule of the Month: Adrenergic Receptors. (n.d.). Retrieved February 6, 2020, from https://pdb101.rcsb.org/motm/100

ANY QUESTIONS?