WEEK 9 (Enzyme-coupled receptors) Flashcards
What are receptors?
- Receptors are proteins associated with cell membranes or located within the cell
- Receptors “recognise” signalling molecules by binding to them
- Binding of receptors by signalling molecules -> Cell behaviour changes
What are the three main classes of Cell-surface Receptors?
- Ion-channel-coupled receptors
- G-Protein-coupled receptors
- Enzyme-coupled receptors
What is the function of Ion-channel-coupled receptors?
They change the permeability of the plasma membrane to selected ions, altering the membrane potential and producing an electrical current
What are Transmitter-gated ion channels?
Ion-channel-coupled receptors that open in response to the binding of an extracellular signal molecule
Describe how Ion-channel-coupled receptors function in synapses
The released neurotransmitter binds to and opens the TRANSMITTER-GATED ION CHANNELS in the plasma membrane of the postsynaptic cell -> Resulting ion flows alter the MEMBRANE POTENTIAL of the postsynaptic cell -> Converts the chemical signal back into an electrical one
Where are Ion-channel-coupled and G-Protein-coupled receptors important in the body?
- ION-CHANNEL-COUPLED RECEPTORS = electrically excitable cells e.g muscle cells
- G-PROTEIN-COUPLED RECEPTORS = every cell type in the body
How do G-Protein-coupled receptors function?
G-protein-coupled receptor binds its extracellular signal molecule -> Activated receptor signals to a G protein on the opposite side of the plasma membrane -> Turns on/off an enzyme in the same membrane
What are G-proteins?
G proteins (GUANINE NUCLEOTIDE-BINDING PROTEINS) are a family of proteins that act as molecular switches inside cells and are involved in transmitting signals from a variety of stimuli outside a cell to its interior
[BOUND TO GTP = ON; BOUND TO GDP = OFF]
Describe the structure of G-Protein complexes
- Made up of alpha (α), beta (β) and gamma (γ) subunits
- Beta and gamma subunits can form a stable dimeric complex called the BETA-GAMMA COMPLEX
- The polypeptide chain traverses the membrane as seven α helices. The cytoplasmic portions of the receptor bind to a G-protein inside the cell.v
How many GPCRs are there in humans?
More than 700
What are G-protein-coupled receptors also called?
Seven-transmembrane receptors
What are the two most frequent target enzymes for G-proteins?
- ADENYLYL CYCLASE = produces the small intracellular signalling molecule CYCLIC AMP
- PHOSPHOLIPASE C = generates the small intracellular signalling molecules INOSITOL TRIPHOSPHATE and DIACYLGLYCEROL
How do G-proteins become activated?
An activated GPCR activates G proteins by promoting the α subunit to eject its GDP and pick up GTP
How is the G-protein anchored to the plasma membrane?
Both the α and γ subunits of the G protein have covalently attached lipid molecules that anchor it to the plasma membrane
How do G-proteins become inactivated?
Activated α subunit interacts with its target protein -> It activates that target protein for as long as the two remain in contact -> The G-protein α subunit switches itself off by hydrolysing its bound GTP to GDP
Describe Cholera
Cholera is caused by a bacterium that multiplies in the human intestine where it produces CHOLERA TOXIN. Condition leads to death unless steps are taken to replace lost water and ions.
MECHANISM: CHOLERA TOXIN enters the cells that line the intestine and modifies the α subunit of a G protein called Gs -> Modification prevents Gs from hydrolysing its bound GTP which locks the G protein in the active state in which it continuously stimulates ADENYLYL CYCLASE -> In intestinal cells, stimulation causes a PROLONGED and EXCESSIVE outflow of Cl- and H2O into the gut -> Catastrophic DIARRHOEA and DEHYDRATION
Describe how acetylcholine slows the heart rate
Acetylcholine binds to its GPCR on the heart cells which activates the G protein Gi -> Activated βγ complex directly opens a K+ channel in the plasma membrane which increases the cell’s permeability to K+ -> Makes the membrane harder to activate which slows the heart rate
Describe how Cyclic AMP is synthesised and degraded
SYNTHESIS = two phosphate groups from ATP is removed and joins the ‘free’ end of the remaining phosphate group to the sugar part of the AMP molecule
DEGRADATION = Breaks the new bond forming AMP
Why do G-Protein-coupled receptor reactions occur rapidly?
Because the reactions do not involve changes in gene transcription or new protein synthesis
[in contrast, responses that involve changes in gene expression are slow]
What is the difference between Cyclic AMP responses in heart and skeletal muscle tissue?
EXTRACELLULAR SIGNAL MOLECULE: Adrenaline
TARGET TISSUE: Heart
MAJOR RESPONSE: Increase in heart rate and force of contraction
EXTRACELLULAR SIGNAL MOLECULE: Adrenaline
TARGET TISSUE: Skeletal muscle
MAJOR RESPONSE: Glycogen breakdown
What is the difference between Cyclic AMP responses in fat and adrenal gland tissue?
EXTRACELLULAR SIGNAL MOLECULE: Adrenaline + Glucagon
TARGET TISSUE: Fat
MAJOR RESPONSE: Fat breakdown
EXTRACELLULAR SIGNAL MOLECULE: Adrenocorticotropic hormone (ACTH)
TARGET TISSUE: Adrenal gland
MAJOR RESPONSE: Cortisol secretion
What is the difference between Phospholipase C responses in liver and pancreas tissue?
EXTRACELLULAR SIGNAL MOLECULE: Vasopressin
TARGET TISSUE: Liver
MAJOR RESPONSE: Glycogen breakdown
EXTRACELLULAR SIGNAL MOLECULE: Acetylcholine
TARGET TISSUE: Pancreas
MAJOR RESPONSE: Secretion of amylase
What is the difference between Phospholipase C responses in smooth muscle and blood platelets?
EXTRACELLULAR SIGNAL MOLECULE: Acetylcholine
TARGET TISSUE: Smooth muscle
MAJOR RESPONSE: Contraction
EXTRACELLULAR SIGNAL MOLECULE: Thrombin
TARGET TISSUE: Blood platelets
MAJOR RESPONSE: Aggregation
Describe how Inositol Phospholipid opens Ca2+ channels
Two small messenger molecules are produced when a membrane INOSITOL PHOSPHOLIPID is hydrolysed and activates PHOSPHOLIPASE C -> INOSITOL 1,4,5-TRIPHOSPHATE (IP3) diffuses through the cytosol -> Triggers the release of Ca2+ from the ER by binding to and opening special Ca2+ channels in the ER membrane
What are growth factors?
Extracellular signal proteins that regulate the growth, proliferation, differentiation and survival of cells in tissues
Enzyme-coupled receptors regulate cell’s ____________
- Growth
- Proliferation
- Differentiation
- Survival
What are Enzyme-coupled receptors?
Transmembrane proteins that display their ligand-binding domains on the outer surface of the plasma membrane
What are Receptor tyrosine kinases (RTKs)?
Enzyme-coupled receptors that consist of a cytoplasmic domain that functions as a TYROSINE PROTEIN KINASE which phosphorylates particular tyrosines on specific intracellular signalling proteins
Which second messenger signals the release of Ca2+ from endoplasmic reticulum?
IP3 - Inositol Triphosphate
What is a short-lived messenger that acts by stimulating a soluble guanylyl cyclase, raising cGMP and stimulating PKG?
NO - Nitric Oxide
Explanation: NO is synthesised from the amino acid arginine and diffuses readily from its site of synthesis into adjacent smooth muscle cells, where it regulates the activity of specific proteins, causing the muscle cells to relax
GPCR is comprised of ___________
7 Transmembrane helices
What are the two most frequent target enzymes for G proteins?
- ADENYLYL CYCLASE = produces cyclic AMP
- PHOSPHOLIPASE C = generates Inositol triphosphate and diacylglycerol -> IP3 promotes the accumulation of systolic Ca2+
What is Guanine-nucleotide exchange factor (GEF) and how does it produce G proteins?
- Induces the GP to release GDP and bind GTP
- Contact with GP results in conformational change that causes GDP to be released
Which receptor binds epinephrine and stimulates a signalling pathway that can ultimately control the contraction of the heart?
B-adrenergic receptor
What is a family of G proteins that activates phospholipase C?
Gq
What do effector proteins lead to changes in?
- Altered metabolism
- Altered gene expression
- Altered cell shape or movement
What happens after the trimeric G-protein becomes active (switched on)?
The alpha subunit dissociates from both the beta and gamma subunits and the receptor
What do the newly activated beta and gamma subunits do when they dissociate?
They open ion channels
