LECTURE 9

Question 1

Structure of adrenoreceptors

Answer 1

• Part of family of G-protein coupled receptors (metabotropic receptors)
• Integral membrane protein
• Single polypeptide chain: 400-500 amino acids
• 7 transmembrane alpha helices
• Binding site buried within a cleft between alpha helices (within plane of membrane)

Question 2

G-protein coupled receptors

Answer 2

• Site-directed mutagenesis experiments have shown that the long third cytoplasmic loop is the region of the receptor that couples to the G protein
• Differences in the sequence of the long third cytoplasmic loop are the basis by which alpha and beta adrenoceptors interact with different G proteins and produce different cellular effects
• GDP –> GTP causes alpha subunit to dissociate and attach to target protein to cause effect

Question 3

Alpha-1 adrenoceptor

Answer 3

• Coupled to phospholipase C-B
• A-1 adrenoceptors are couples to the G protein Gq
• Alpha subunit of Gq activates phospholipase C-B (PLC)
• PLC acts on the membrane phospholipid PIP2 (phosphatidyl inositol bisphosphate)
• Produces 2 products
  1. Inositol trisphosphate (IP3)
  2. Diacylglycerol (DAG)
• IP3 releases Ca2+ from the endoplasmic reticulum
• DAG activates protein kinase C (phosphorylates various cellular proteins)

Question 4

Alpha-2 adrenoceptor

Answer 4

• Inhibition of adenylyl cyclase
• A-2 adrenoceptors are couples to the G protein Gi
• Alpha subunit of Gi inhibits adenylyl cyclase (AC)
• Since AC converts cellular ATP to cAMP, cAMP levels are decreased
• Since cAMP activates protein kinase A (PKA), there is reduced activity of PKA
• Hence there is reduced phosphorylation of certain intracellular proteins
• This produces the effect e.g. inhibition of transmitter release from autonomic nerve terminals

Question 5

Beta-adrenoceptors

Answer 5

• Stimulation of adenylyl cyclase
• B adrenoreceptors are coupled to the G protein Gs
• Alpha subunit of Gs stimulates adenylyl cyclase (AC)
• Since AC converts cellular ATP to cAMP, cAMP levels are increased
• Since cAMP activates PKA, there is increased activity of PKA
• Hence there is enhanced phosphorylation of certain intracellular proteins
• This produces the effect e.g. relaxation of smooth muscle

Question 6

Functions of adrenoceptors in the heart

Answer 6

B-1 subtype 
SAN - increased heart rate
AVN - increased conduction velocity 
Atria - increased contractility 
Ventricles - increased contractility and enhanced automaticity

Question 7

Uses of alpha-adrenoceptor antagonists

Answer 7

• Hypertension
• Benign prostatic hypertrophy
• Phaeochromocytoma

Question 8

Uses of beta-adrenoceptor antagonists

Answer 8

• Cardiovascular
• Glaucoma
• Thyrotoxicosis
• Anxiety states
• Migraine prophylaxis
• Benign essential tremor

Question 9

Effects of B-adrenoceptor antagonists

Answer 9

• Bronchoconstriction
• Worsening of pre-existing cardiac failure
• Bradycardia
• Heart block
• Hypoglycaemia
• Physical fatigue
• Cold extremities
• Bad dreams