Tissues- Signalling between cells II Flashcards
What are hormones referred to and why
Chemical messages involving hormones are often referred to as ligands as they exert their effects by binding to receptors.
What are receptors
Receptors are usually proteins that bind to chemical mediators known as ligands and upon activation they elicit an effect within a cell. The intracellular effect evoked by an occupied receptor usually arises due to any chemical messenger that is a separate entity from the receptor or ligand- second messenger
Describe ionotropic receptors
Ionotropic receptor
Ligand binding opens ion permeable pore traversing the membrane
Describe G-protein coupled receptors
membrane
G-protein coupled receptor
Ligand binding activates intracellular G-protein
Describe enzyme-linked receptors
Ligand binding receptor clustering activates internal enzymes
Describe intracellular receptors
A membrane permeable ligand binds to receptor inside cell
Describe the signal transduction events that take place in ionotropic receptors
Ligand binds to the transmembrane receptor protein via the ligand binding domain on the external surface of the receptor.
Change in conformation of channel protein opening of a pore (incorporated within its quaternary structure)
Pore allows ions to move in or out of cell according to their respective concentration gradients
theList some examples of ionotropic receptors
Receptor: Nicotinic Acetylcholine
Ligand: Acetylcholine (ACh)
Location: Skeletal muscle, Brain
Physiological effect: Muscle contraction, Cognitive enhancement
Receptor; GABAa
Ligand: -amino butyric acid (GABA)
Location: Neuronal
Physiological effect: neuronal excitability (inhibition)
Receptor: NMDA
Ligand: Glutamate
Effect: Synaptic plasticity and memory formation
5-HI3
5-HT
Anxiety
What can disfunctions in the nicotinic acetylcholine receptor lead to
Muscle and brain problems
Describe the resting state of the G-Protein complex
In the resting state the G protein consists of a Ga subunit, an Gby subunit, and an associated GDP molecule (not part of heterotrimer), which are in close proximity to the 7-Transmembrane receptor
Describe the 7-TM receptor
Crosses the plasma membrane 7 times, linked to the intracellular G-protein complex.
Describe the signal transduction events of G-protein receptors
7-TM receptor & heterotrimeric G-protein are inactive
Ligand binding changes conformation of receptor
Unassociated G-protein binds to the receptor
bound GDP molecule is phosphorylated to GTP
GDP is exchanged for GTP
G-protein dissociates into two active components:
-subunit- a
subunit- by
bind to their target proteins (both act as distinct second messengers)
Internal GTPase activity on -subunit dephosphorylates GTP GDP- when ligand dissociates from receptor
-subunit dissociates from target protein inactive again
Receptor remains active as long as ligand is bound and can activate further heterotrimeric G-proteins
Ga and Gby subunits re-associate and are once again available to the receptor.
Why is GDP exchanged for GTP
It is not energetically favourable for the GDP to be bound to the target protein.
Describe the variation in the G alpha subunits
There is significant variation between the G alpha subunits, separated into 3 categories which are associated with alternative signal transduction pathways. The Gby subunit is also physiologically active.
Describe the three different types of Ga subunits
Subunit: Gaq 2nd messenger: Phospholipase Downstream effect i: PIP2 hydrolysed into IP3 and DAG Downstream effect 2: IP3 promotes Ca2+ release from intracellular stores, DAG activates non-selective ion channels Example: AT-1 angiotensin receptor Effect: vasoconstriction Gi protein linked receptor Inhibits adenylyl cyclase Reduces levels of PKA Example: M2-muscarinic receptor Effect: heart rate Gs protein linked receptor Stimulates adenylyl cyclase Converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) cAMP activates protein kinase A (PKA) Example: 1-adrenergic receptor Effect: heart rate
What is meant by phosphorylation
Addition of a PO4 group- carried out by kinases and activates a number of protein enzymes
What is meant by dephosphorisation
Removal of a PO4 group- carried out by phosphatases, deactivates a number of protein enzymes.
Describe the characteristics of enzyme-linked receptors
Transmembrane receptors that normally consist of one transmembrane domain, which has a ligand-binding domain on the outside, and specialised enzymes (tyrosine kinase) on the outside. These receptors do not ordinarily work alone and require clustering of more than one receptor protein to activate the intracellular enzyme. Once activated, the intracellular enzyme will activate a signalling cascade inside the cell.
Describe the signal transduction pathways of enzyme-linked receptors
Ligand binding receptors clustering
Receptor clustering activates enzyme activity within cytoplasmic domain
Enzymes phosphorylate receptor
Phosphorylation binding of signalling proteins to cytoplasmic domain
These signalling proteins recruit other signalling proteins signal is generated within cell
The signal is terminated when a phosphatase dephosphorylates the receptor
List examples of enzyme-linked receptors
Tyrosine kinase
Insulin receptor (CD220 antigen)
Ligand: Insulin
Physiological effect: Glucose uptake
ErbB receptors
Ligand: Epidermal Growth Factor, Transforming Growth Factor
Physiological effect: Cell growth, proliferation
Guanylyl-cyclase linked receptors
NPRA
Ligand: Atrial/ Brain natriuretic peptide
Physiological effects: Vasodilation; Blood pressure
Ser/Thr-kinase linked receptors
TR1
Ligand: Transforming growth factor beta
Physiological effect: Apoptosis
Describe how steroid hormones secrete their actions
Steroid hormones are membrane permeable (hydrophobic, lipophilic) and therefore excrete their actions on intracellular receptors. IC receptors are essentially transcription factors and hence regulate mRNA and transcription.
Describe the two types of intracellular receptors for steroid hormones
Type 1; locates within cytosolic compartment and are associated with chaperone molecules- usually heat shock proteins. Once the hormone binds to the receptor the heat shock protein molecule dissociates allowing the hormone-receptor complex to form a homodimer with another hormone-complex receptor. The homodimer subsequently translocates to the nucleus where it binds to DNA and acts as a transcription factor.
Type 2: Located within the nucleus
Binding of hormone ligand transcriptional regulation
List examples of intracellular receptors
Type 1 - Glucocorticoid receptor
Ligands: Cortisol, corticosterone
Physiological effect: immune response, Gluconeogenesis
Type 2 - Thyroid hormone receptor
Ligand: Thyroxine (T4), triiodothyronine (T3)
Physiological effect: Growth & development
Era, Estradiol, Cytosolic, Female sexual development
