L9 Pharmacodynamics II Flashcards
What are the two general potential responses to a drug binding to an intracellular receptor?
- Stimulate an intracellular enzyme
2. Regulate the cellular localization of the receptor and alter gene transcription (gene active receptor)
What are the two major therapeutic consequences of gene active receptors?
- Lag period (30 min to a few hours) before the effects may be observed due to the time it takes to synthesize new proteins
- Effects may persist for hours or days after the agonist is gone (slow turnover of enzymes or proteins synthesized)
What are the three general types of plasma membrane receptors?
- Ligand-regulated transmembrane enzymes (protein tyrosine kinase and cytokine receptors)
- Ligand-gated channel receptors
- G-protein family
Describe the structure of a ligand-regulated transmembrane enzyme receptor.
Receptor polypeptide crosses the membrane once and has an extracellular binding domain and an intracellular enzymatic domain (tyrosine/serine kinase or guanylyl cyclase)
Describe the series of events when a ligand binds to the extracellular domain of a ligand-regulated transmembrane enzyme receptor.
- Conformational change
- Dimerization
- Activation
- Downstream phosphorylation of proteins
___ of tyrosines on the receptor’s cytoplasmic side can intensify or prolong the duration of receptor activation.
Autophosphorylation
Ligand-regulated transmembrane enzyme receptors can be down-regulated via ___.
Endocytosis
What are three endogenous substances that utilize tyrosine kinase receptors?
- Insulin
- Epidermal growth factor (EDF)
- Atrial naturitic factor (ANF)
How is a cytokine receptor different from a tyrosine kinase receptor?
Utilize a separate tyrosine kinase that binds non-covalently and is not intrinsic to the receptor
What are the activation steps of a cytokine receptor?
- Ligand binding
- Conformational change
- Receptor dimerization
- JAKs are activated and phosphorylate tyrosine residues on the receptor
- Phosphorylation of tyrosine facilitates binding of STAT
- JAK phosphorylates STAT
- STATs dimerize, dissociate, and travel to the nucleus to regulate gene transcription
Describe the structure of ligand gated channel receptors.
Pentamer, 4 types of glycoprotein subunits (2 alpha, beta, gamma, delta) that form a cylindrical structure w/a channel
Describe binding to the nicotinic cholinergic receptor.
ACh binds to the alpha subunits, produces a conformational change, and opens the channel, allowing Na into the cell.
What are some neurotransmitters that signal via ligand-gated receptor mechanisms?
ACh, excitatory amino acids (gluamate and asparate), and GABA
Describe the structure of G-protein linked receptors.
Single polypeptide chain that traverses the plasma membrane 7 times; amino terminus is extracellular and carboxy terminus is intracellular
Which part of the G-protein linked receptor contains the pharmacophore?
Extracellular region
Which part of the G-protein linked receptor regulates the ability to interact with G-proteins?
Third intracellular loop
Which part of the G-protein linked receptor contains sites that are subject to phosphorylation and regulation?
Carboxy terminus
What types of NT use G-protein linked receptors?
DA, NE, 5-HT, ACH
Describe the activation of G-proteins.
- Ligand binds, conformational change
- Activated receptor binds G protein
- Conformational change leads to dissociation of GDP and binding of GTP
- GTP binding triggers dissociation of G-alpha from the receptor and the beta-gamma subunit
- Action
- GTP hydrolized to GTP, re-dimerization
What is the primary mediator of activating second messengers?
G-alpha-subunit
Describe the activation of adenylyl cyclase.
- Ligand binding
- G-protein activation
- Adenylate cyclase activated
- Adenylate cyclase catalyzes formation of cAMP
- cAMP activates protein kinase
- Kinase activity –> response
Describe the activation of the phophoinositide hydrolysis pathway.
- Ligand binding
- G-protein activation
- PLC activation
- PLC cleaves PIP2 into DAG and IP3
- IP3 opens calcium channel, allowing calcium to flow out of the ER
- Calcium binds calmodulin to form a kinase, which phosphorylates things
- DAG forms PKC, which also phosphorylates things
Describe the possible effects of one drug at one receptor.
- Beneficial (anti-coagulant activity)
- Toxic (excessive bleeding)
Strategies: manage dose, monitor effect
Describe the possible effects of one drug at the same receptor in different tissues.
- Beneficial at one tissue
- Toxic at another
Strategies: add another drug to lower dose of first drug, give lowest dose to achieve effect, limit effects via route of administration
