Siganl Transduction (7) Flashcards
What are the three maintain types of cell surface receptors?
- Ligand gated
- Intrinsic enzymatic activity receptors
- G protein coupled receptors (GPCR)
Where are the majority of receptors found and what are the anomalies?
- On cell surface
- Steroid and thyroid hormones are intracellular
What is meant by an agonist to a GPCR?
- Binds and causes activation of a receptor
- May lead to intracellular signal transduction events
Give examples of GPCR agonists.
- Anti-asthma: B2 adrenoceptor agonists
- Analgesia/anaesthesia: u-opioid receptor agonists
What is meant by antagonists?
- Bind to receptor and don’t activate receptor
Give examples of antagonists
- Cardiovascular: B adrenoreceptor antagonists (Beta blockers)
- Neuroleptics: D2 dopamine receptor antagonists
When there are diseases that are associated with signal transduction what is this normally caused by in a general term?
- Mutations to GPCRs
Give three examples of diseases associated with signal transduction. And what do they cause?
- Retiritis pigmentosa: loss of function of rhodopsin
- Nephrogenic diabetes insipidus: loss of function mutations to V2 vasopressin receptor
- Familial male precocious puberty: gain of function of LH receptor.
Give examples of GPCRs.
- Sensory: light/odour/tastes
- Ion: H/Ca
- Neurotransmitter: ACh/glutamate
- Peptide and non peptide hormones: glucagon/adrenaline
- Large glycoproteins: TSH
Outline the structure of GPCRs.
- Single polypeptide chain (300-1200aa)
- 7 transmembrane spanning regions
- Extracellular N-terminal
- Intracellular C-terminal
- Ligand binding regions
What are the ligand binding regions in a GPCR?
- Transmembrane domain
- N-terminal region
Once an agonist has bound to a GPCR what happens?
- Activated GPCR interacts with a G protein
- G protein contains alpha/beta/gamma subunits (heterotrimeric)
- GPCR-G protein interaction activates G protein by the exchange of GTP for GDP on the G protein alpha subunit
- a-BY complex dissociates into a-GTP and free BY
- These then interact with effector proteins-either 2nd messenger-generating enzymes or ion channels
How is G-protein signalling terminated?
- a-GTP and BY interaction with effectors lasts until a-GTPase hydrolyses GTP->GDP
- a-GDP can then join to BY to form an inactive molecule
What governs receptor G protein selection?
- Activated GPCRs preferentially interact with specific types of G protein, G-alpha subunit’s a primary determinant
- In turn, G-alpha subunits and GBY subunits interact with specific effector proteins
Give examples of effectors of G proteins.
- Enzymes: adenylyl cyclase for ATP -> cAMP
- Ion channels: voltage operated Ca channels (VOCC)
G protein-regulated inwardly-rectifying K channels (GIRKS)
Outline the agonist stimulated regulation of adenylyl cyclase.
- cAMP production from ATP using adenylyl cyclase
- cAMP dependent protein kinase (PKA)
- Epacs (guanine nulceotide exchange factors)
- Cyclic-nucleotide-gated ions channels (CNGs)
Give examples of Gs coupled receptors and what does Gs stand for?
- Gs: G-protein stimulatory
- B-adrenoceptors
- D1 dopamine receptors
- H2 histamine receptors
What is meant by Gi?
Give examples of Gi-coupled receptors.
- G protein inhibitory
- a2 adrenoceptors
- D2 dopamine receptors
- u-opioid receptors
How does cAMP exert the majority of its actions?
- Via cAMP-dependent protein kinase (PKA/A-kinase)
Outline the agonist stimulated regulation of phospholipase C.
- Agonist binds to GPCR
- alpha-q GTP unit splits from BY and joins to phospholipase C
- This forms PIP2
- This then splits to form DAG and IP3
- An IP3 receptor on the Endoplasmic reticulum to stimulate the release of Ca
- Ca then joins onto PKC which binds onto the DAG molecule.
Give examples of Gq coupled receptors.
- a1 adrenoceptors
- M1 muscarinic receptors
- H1 histamine receptors
Outline how signal amplification may occur.
- B-adrenoceptor -> Gs protein -> adenylyl cyclase part of cascade causes little amplification
- Activation of anenylyl cyclase generates many molecules of cAMP -> activates enzyme PKA
How can positive inotropy be caused?
- Adrenaline and sympathetically reused noradrenaline can interact with ventricular B1-adrenoceptors to increase force of contraction
- cAMP-dependent protein kinase stimulates VOCC channel
- Increased Ca -> increased contractility
How does smooth muscle contract in relation to adrenoceptors?
- Sympathetically released NA interacts with vascular smooth muscle alpha 1 adrenoceptors -> vasoconstriction
- Parasympathetically released ACh interacts with bronchiolar smooth muscle M3-muscarinic receptors -> bronchoconstriction
How is neurotransmitter release modulated?
- CNS and PNS neurotransmitter release is often modulated by presynaptic GPCR
- GBY inhibit VOCCs reducing Ca influx and neurotransmitter release
