Receptor Theory Flashcards
Receptor Type- Based on Molecular Structure (7 of them)
- GPCRs; Seven transmembrane receptors
-Ligand-Gated Channels; Chanel opens when something binds to them
-Ion Chanels; Do not need a ligand
-Catalytic Receptors: Catalyze an enymatic response (RTK)
-Nuclear Receptors; Located in the nucleus
-Transporters; Transport from one side of cell to another
-Enzymatic; The enzyme w/in the cell is the target
Generic Cell Signaling Process
-Signaling molecule (1st messenger) binds to the receptor and sends an intracellular response
-Signaling molecule can be the drug or an endogenous ligand
-Signal transduction proteins activate–> this leads to second messenger activation –> which then lead to the effector protein being activated
Lag period vs Persistence
-Lag Period: Response takes 30+ minutes to several hours. This typically requires transcription/translation (so mrna drug)
Persistence: Response hangs around for hours to days. Protein degradation pathways vary in each person
Generic Phosphorylation Cascade
Drug binds to receptor–> conformational change takes place–> inactive protein kinase becomes active protein kinase–> phosphate groups are added to protein
4 Transmembrane Signaling Methods
(How do we get our message into the cell?)
- A lipid soluble ligand that crosses the cell membrane and acts on an intracellular receptor
- Ligand regulated transmembrane enzymes: Transmembrane receptor that binds and stimulates intracellular tyrosine kinase.
-Require signaling by insulin, growth factors, ANP - A ligand-gated transmembrane ion channel (ex. ACh, serotonin, GABA receptors)
- GPCR
Mechanism of GPCR Signaling
Drug or endogenous ligand binds to receptor
–>receptor undergoes conformational change which activates the alpha subunit & binds GDP (inactive) –>GTP (Active) –> GTP activates the effector/signaling protein
–>activates the second messenger –>downstream process
Structure of GPCRs
-Binding to the receptor actives the G-protein (guanine nucleotide binding protein).
GDP –>GTP
-Receptor has seven transmembrane alpha-helices
-Binds to the active site on the cell wall, interacts with the G-protein inside the cell
-Trimeric, have three subunits; alpha (binds to GDP, activates GTP) beta, gamma
Structure of RTKs
-Ligands are growth factors or adhesion factors
-Ligand binding stimulates
-Dimerization (two monomers forming one dimer)
-This then causes phosphorylation of tyrosine molecules on dimer (uses 6 ATP) –> downstream cascade of effects
Describe the role of second messengers. List a few examples of common ones
-Second messengers play an important role in activating an effector protein or starting the downstream cascade of effects once a receptor is bound by a ligand or drug
-cAMP: Exerts most of it’s effects by phosphorylation (this uses ATP); mobilizes stored energy, increases rate & force of contraction
-Phospholipase C splits PIP2 into DAG and IP3
DAG activates protein kinase C
IP3 triggers the release of Ca++
Desensitization, and how it works in the GPCR
Desensitization is the process of stopping the signaling cascade after a ligand has bound to a receptor.
Ex in a GPCR: Ligand binds to receptor–>undergoes a conformational change (now in the open confirmation) –>The carboxyl end of the receptor has OH groups hanging off it within the cell –>Alpha subunit on the g-protein floats away, activating GDP –>GTP. GTP activates adenylyl cyclase–> cAMP (second messenger) is activated –>downstream cascade of effects.
If the ligand forms a covalent bond, there are two options:
1. Beta-arestin binds to the OH groups on the carboxyl end of the receptor, drags it along the cell membrane to a clarithen coated pit. The pit engulfs the receptor, separates the receptor and ligand, and the receptor is recycled
2. If the bond cannot be broken, lysosomes will use their acidic, digestive enzymes to break up the receptor into it’s smaller AA counterparts and release those to be reused in the cell.
Catalytic Cell-Surface Receptors
-Membrane bound, activated by drug or endogenous ligand
-Either directly associated with an enzyme, or the receptor itself is an enzyme
-Tyrosine kinase
-Tyrosine phosphatase
-Serine/Threonine Kinase
-Guanylate cyclase
Tyrosine is 1/20 AA, Kinase= adds a phosphate, Phosphatase= strips a phosphate
Voltage Gated Ion Channel
-Ion specific channels (Na+, K+, Ca++, Cl-)
-Can be fast or slow, depends on the ion and the gradient
-Found in excitable cells; neurons, muscle, endocrine
-Closed at resting membrane potential
- Na + Channel has two gates- Gate 1 opens when threshold is reached –> Gate two immediately inactivates (regulates how much of each ion can pass through) –> deactivates (both gates closed), then circles back to closed
Ligand Gated Ion Channels: Inotropic vs Metabotropic
Inotropic:
-Most common
-Ligand binding site & channel are on the same protein
-Ligand binds, channel opens
Ex: Nicotinic aCH receptor
Metabotropic:
GPCR in close proximity to the ion channel
-Ligand binds to the site –> activates GPCR –> second messenger activity opens ion channel
Ex: Olfactory nerve, scents/smell
Receptors Inside the Cell
(2 of them)
-Must be a gas or lipid soluble
Ex: Blood vessels lined with endothelial cells–> strong shearing force/turbulent blood flow against the endothelial cells–> activates nitric oxide synthase –> nitric oxide is produced–> diffuses out to smooth muscle (can freely diffuse across the cell membrane)–> relaxes smooth muscle, opens blood vessel
Steroid Hormones: Can freely diffuse across membrane because they are lipid soluble and uncharged
Steroid hormone binds to steroid receptor-> migrates to nucleus–> binds to steroid regulatory elements in the nucleus and increase transcription and translation of genes
