Receptor bias and sensitization

How can a GPCR be biased?

can be G-protein biased, balanced (unbiased), B-arrestin biased

Describe the GRK + arrestin GPCR pathway

(1) agonist binds to GPCR

(2) GRK2 +P the GPCR, preventing receptor interaction with G-protein and promoting B-arrestin recruitment

(3) Receptor-arrestin complex binds to coated pits which promotes receptor internalization, simultaneously promoting receptor desensitization

(4) Agonist either dissociates when receptor-arrestin complex internalized which reduces arrestin association and promotes phosphatase action OR depending on the receptor and agonist concentration intracellularly, a second phase of G-protein activation can occur before the receptor is recycled to the PM

Receptor internalization

receptor moves from PM to the inside of the cell via endosomes

Receptor recycling

process by which receptors that were once internalized are returned to the PM (resensitization)

How can receptor bias be used therapeutically?

can design ligands to favor biased agonism to elicit desired responses after binding to a receptor

Receptor sequestration

receptor internalized

Receptor downregulation

long-term reduction of the number or density of receptors

How can receptors be downregulated?

internalized and degraded via lysosomes

Receptor inactivation

receptor inactivated by some agent

Signaling protein mediated inactivation

receptor inactivated by a signaling protein

Homologous desensitization

ligand-dependent process where only the specifically activated receptor is desensitized while other receptors remain fully responsive

Heterologous desensitization

ligand-independent effect where activation of one receptor type leads to the desensitization of other distinct receptor types on the same cell even if those receptors are unoccupied

Tachyphylaxis

rapid and sudden decrease in response to repeated doses of a drug over a short time period, largely driven by receptor desensitization

drug essentially doesnt work anymore

Receptor upregulation

process of increasing the number of receptors on the cell’s surface (which typically occurs when there is prolonged deprivation of a ligand so the receptor number is increased to increase sensitivity to available ligands)

Hypersensitivity (of a receptor)

enhanced cellular response to a ligand due to either receptor upregulation or the unmasking of previously hidden receptors

Tolerance

body’s reduced response to a drug due to prolonged receptor downregulation so the body will needed larger doses to achieve the same initial effect

Withdrawal symptoms

physiological responses that occur when a chronically administered drug is suddenly stopped

How does upregulation and downregulation of a receptor affect dose-response curve?

upregulation - shift to left without changing ED50, increase in Emax

downregulation - shift to right without changing ED50, decrease Emax

How does sensitization and desensitization of a receptor affect dose-response curve?

sensitization - shifts curve to left but Emax doesnt change

desensitization shifts curve to right but Emax doesnt change