03 - Cell Receptors and Messengers

Question 1

One important clas of plasma bound proteins is receptors. How does the structure of these receptors determine what ligands they will bind and the relative strength of this binding?

Answer 1

Specificity of receptor: The ability for that receptor to bind only one type or a limited number of structurally similar types of chemical messengers (ligand); the shape and charge associated with the receptors determines how well the ligand will bind - the strength is called affinity (stronger with complimentary shape and opposite charges).

Question 2

How are receptors modulated to increase or decrease their affinity for a ligand?

Answer 2

Receptor proteins can change shape to chage their protein-ligand affinity either by charge distribution or bonding between amino acids.
Allosteric modulation: When a protein contains two binding sites, a second ligand can bind to a regulatory site, which is separate from the active site, resulting in conformational changes in the protein that can incerase or decrease the affinity of the active binding site.
Covalent modulation: Covalent bonding of chemical groups to the receptor can change its shape.

Question 3

What functions are associated with the extracellular, intracellular, and transmembrane domains of a receptor?

Answer 3

Extracellular: Binds chemical messengers endowing specificity, may have multiple binding sites, binding of the outside causes changes in enzymatic activity inside.
Transmembrane: Contains hydrophobic portions of the receptor.
Intracellular: Contains amino acid segments where the receptor can be phosphorylated and thereby regulated by intracellular substances.

Question 4

How might a gene mutation that changes the amino acid sequence impact receptor function?

Answer 4

Changes in the structure of extracellular and intracellular portions can change the function of the protein in the signaling pathway or transport mechanism. A mutation can alter the specificity and affinity messengers have with a receptor. It can also change the shape of the protein where the messenger can no longer bind.

Question 5

What are differences in the sites of action of a lipid-soluble and water-soluble first messenger? Contrast the roles and site and mechanism of action of first and second messenger (in the case of water-soluble)

Answer 5

Lipid-soluble messenger: Message can go straight to nuclear or cytoplasmic receptor and initiate a cellular response (usually increased gene transcription). Messengers are transported on a water-soluble protein carrirs and then moves unimpeded through the membrane to the receptor. Examples: Steroids, thyroid hormones, progesterone, etc.
Water-soluble messenger: Message must bind to plasma membrane receptor. This will activate the protein and activate a second messenger which will initiate a cellular response. Water-soluble ligands (first messenger) bind to specific receptors on extracellular surface. Second messengers are substances that enter or are generated in cytoplasm as a result of receptor activation from first messenger.

Question 6

Intracellular cascades regulate some of cell’s most critical functions. Describe how cyclic AMP (cAMP) and calcium can have such diverse mechanisms of action within the cell. What is a third major second messenger system and how does it relate to the other two? (Table 3.4.1)

Answer 6

Take home points (remainder on table)…
Variety of effects: Second messengers activate protein kinases which phosphorylate a variety of proteins (specific to that cell type) responsible for different function.
Crazy amplification: The cell response is widely distributed (eg simple cAMP will activate a lot of PKA, which will phosphorylate and activate even more proteins).

Question 7

Describe how the synthesis of eicosanoids is regulated. How can this pathway be manipulated by pharmacological intervention? (Table 3.5.1)

Answer 7

Pharmacological intervention (remainder on table) -
COX inhibitors: Aspirin and NSAIDs block production of endoperoxides, prostaglandins (PGE, PGA), and thromboxanes.
Phospholipase A2 inhibitor: Steroids block all eicosanoid production.
LOX and leukotriene inhibitors: Used to prevent production and/or actions of leukotriene in treating asthma.