Receptor Effector Coupling

Question 1

Receptor

Answer 1

Macromolecule made of proteins that interact with endogenous ligand or exogenous drug to mediate a pharmacological/physiological effect

Question 2

Effector

Answer 2

Downstream molecules that transduce drug-receptor interaction to cellular effect

Question 3

Lipid-soluble ligands and intracellular receptors

Answer 3

Receptors located in the cytosol/nucleus, ligands are lipid soluble to cross the membrane (steroids, gases), upon binding receptors activate and translocate to the nucleus, bind to DNA sequences to promote gene transcription

Question 4

Components of intracellular receptors

Answer 4

Ligand-binding domain, DNA-binding domain, transcription-activating domain, kept inactive by chaperone proteins (hsp90), dissociates when ligand binds

Question 5

Steroids

Answer 5

Usually bound to carrier protein in circulation, dimerization of receptors, binding to DNA, protein synthesis, slow effect, response persists for hours to days

Question 6

Nitric oxide (NO)

Answer 6

Bioactive gas, rapidly crosses the membrane, stimulates soluble guanylate cyclase, generates cGMP, leads to vasodilation

Question 7

Transmembrane receptors with intrinsic enzymatic activity

Answer 7

Ligands are trophic hormones (EGF, TGFbeta, insulin, PDGF, ANP), span membrane once, has extracellular ligand-binding domain and cytoplasmic enzyme domain (tyrosine kinase, serine kinase, or guanylyl cyclase)

Question 8

Mechanism of action of transmembrane receptors with intrinsic enzymatic activity

Answer 8

Receptor inactive in monomeric form, ligand binds, receptors dimerize, enzymes in close proximity, phosphorylation of receptor, enzymes phosphorylate and activate protein targets

Question 9

Lasting effect of transmembrane receptors with enzymatic activity

Answer 9

Phosphorylation can last 10-20 seconds, receptor remains active after ligand disappears, activation of downstream pathways leads to amplification of signal

Question 10

Termination of signal of transmembrane receptors with enzymatic activity

Answer 10

Ligand dissociation and degradation

Receptor endocytosis for proteolytic degradation- leads to receptor downregulation

Question 11

Transmembrane receptors with no intrinsic activity

Answer 11

Do not contain intrinsic enzymatic activity, respond to peptide ligands (growth hormone, cytokines, interferons), span membrane once, have extracellular ligand-binding domain, Janus-kinase (JAK) binds non-covalently to the receptor

Question 12

Mechanism of action of transmembrane receptors without intrinsic activity

Answer 12

Ligand binds, receptor dimerizes, brings JAK to close proximity, activates JAK, JAK phosphorylates the receptors, signal transducer activator of transcription (STAT) is recruited, JAK phosphorylates STAT, STAT dissociates, translocates to nucleus, activates transcription

Question 13

Lasting effect of transmembrane receptors without intrinsic activity

Answer 13

Effects take minutes to hours, JAK-STAT phosphorylation amplifies signal

Question 14

Termination of signal of transmembrane receptor without intrinsic activity

Answer 14

Ligand dissociation and degradation

Receptor endocytosis for proteolytic degradation- leads to receptor downregulation, receptors must be resynthesized

Question 15

Ligand-gated ion channels

Answer 15

Important for synaptic transmission, natural ligands (acetylcholine, serotonin, GABA, glutamate), increase transmembrane conductance of different ions to alter membrane potential across membrane

Question 16

Nicotinic acetylcholine receptor

Answer 16

5 subunits, alpha subunits contain ligand binding domain, ACh binding causes conformational change, channel opens, sodium crosses membrane

Question 17

G-protein coupled receptors (Gs, Gi, Gq)

Answer 17

Most abundant, crosses membrane 7 times, amino terminus is extracellular, carboxy terminus is intracellular, receptor is coupled to trimeric G-protein with alpha, beta, and gamma subunits

Question 18

Desensitization

Answer 18

GPCR undergoes conformational change after activation/dissociation of G-protein, association of GPCR kinase (GRK), phosphorylates residues on cytoplasmic tail, recruits beta-arrestin protein which prevents G-protein binding, causes internalization of GPCR for recycling

Question 19

Downregulation

Answer 19

Receptors are degraded, must be resynthesized

Question 20

Second messenger

Answer 20

Ligands bind to receptors, triggers activation of G-protein, changes activity of effector which activates second messenger

Question 21

Adenylate cyclase

Answer 21

Activates cAMP (Gs)

Question 22

Guanylate cyclase

Answer 22

Activates cGMP (NO)

Question 23

Phospholipase C

Answer 23

Activates DAG, IP3 (Gq), effector changes 2nd messenger concentration and can amplify or dampen response

Question 24

Gs/Gi second messenger

Answer 24

cAMP, activated by beta adrenergics, glucagon, histamine on Gs, inhibited by alpha2 adrenergics, muscarinics on Gi

Question 25

Gq second messenger

Answer 25

Phospholipase C uses PIP2 to generate DAG and IP3, IP3 causes release of calcium from ER, activated by alpha1 adrenergics, muscarinics, histamine on Gq

Question 26

Second messenger termination

Answer 26

Enzymes terminate 2nd messenger responses by breaking them down

Question 27

cGMP termination

Answer 27

Degraded by phosphodiesterases (inhibited by sildenafil)

Question 28

cAMP termination

Answer 28

Degraded by phosphodiesterases (inhibited by caffeine, theophylline)

Question 29

IP3 termination

Answer 29

Inactivated by dephosphorylation

Question 30

DAG termination

Answer 30

Phosphorylated to a less active messenger called phosphatidic acid by DAG kinase

Question 31

Calcium termination

Answer 31

Actively removed from the cytoplasm by calcium pumps

Question 32

Drugs that do not fit drug-receptor model

Answer 32

Antimicrobials, osmotic diuretics, antacids