Lecture 2 Flashcards
What are some key concepts of intracellular receptors
- receptors are inside the cell, which means the drug has to cross the plasma membrane
- drugs must be lipid soluble
- classic example is steroid hormones
- mode of action is to bind to the LBD of a steroid hormone receptor, leading to displacement of HSP or other chaperone, which exposes a DNA recognition domain and leads to activation of transcription of target genes (receptor enters nucleus and binds DNA)
- slow onset and long lasting effects
What are GPCRs?
transmembrane receptors that are mostly targeted by therapeutic drugs
- When a ligand binds to a receptor, the protein on the other side containing ______,_______ and _______ subunits activate, which causes the _______ subunit bound to ______ changes to _________ and can influence effector proteins; the ________ and ________ stick together and can influence effector proteins
- beta and gamma subunits can influence the activity of a variety of protein types such as ____ _________, usually connected to membranes such as _________, __________.
- GPCR are usually categorized based on the subtype of ________ that is associated. Different ________ subtypes can influence different signaling cascades via effects on _________ __________ (Gs, Gi) or _____________ (Gq).
- alpha,beta and gamma; alpha; GDP; GTP; beta; gamma
- ion channels; increasing K channels and increasing Ca2+ channels
- Galpha; Galpha; adenylate cyclase; phospholipase C (PLC)
What does receptors coupled to Gs do?
- trigger increased activity of AC, leading to production of cyclic AMP, which activates cAMP dependent protein kinases
What does receptors coupled to Gi do?
suppress activity of AC, these responses are generally very quickly and mediate moment to moment control of many physiological functions
What does receptors coupled to Gq do?
- trigger increased activity of PLC, leading to production of inositol triphosphate (IP3) from breakdown of PIP2
- IP3 triggers release of intracellular Ca2+ stores, which can influence a variety of signaling pathways. Other byproducts (DAG) lead to activation of protein kinase C and target substrates to phosphorylze them
What are transmembrane receptors (TKRs)
- are another example of how extracellular ligands can be translated into changes in cellular signaling
- activation of TKRs is driven by dimerization of receptors in the presence of a ligand, causing the receptor to autophosphorylate + become activated
- drugs that inhibit or stimulate the activation of these receptors will influence downstream signaling mechanism
What are ion channels
- fastest mechanism of signaling
- allows ions to cross the plasma membrane very quickly, leading to change in membrane voltage
- different ion channel types are controlled by distinct stimuli, such as ligand binding or changes in membrane voltage. Drugs that target ion channels alter their response to these stimuli or block the flow of ions
What are Voltage gated ion channels
- respond very rapidly to changes in membrane voltage
- movements of charged amino acids in the transmembrane electric field change position in response to changes in voltage
- allows protein to change its activity in milliseconds
What are ligand gated channels
- open or close in response to binding of a small signaling molecule.
- important role in synapses in the CNS. Common drugs for psychiatric conditions target ligand gated channels
How do we describe the effects of a drug?
- Substances can influence receptor activity in a variety of different ways
- agonism means that a substance/drug binds to a receptor and influences its activity. This is usually depicted as a concentration - response curve
What is EC50?
refers to the concentration of drug that yields a 50% maximal effect
What is Emax
maximal biological effect observed with drug
Efficacy
maximal drug effect (Emax)
Potency
refers to the concentration dependence (EC50). a drug with strong potency has a low EC50, a drug with weak potency has a high EC50.
