Pharmacology- Receptors- Effector coupling Flashcards
What are the 4 receptor superfamilies?
- chemically-gated (receptor-operated) ion channels
2•indirect (G-protein mediated) linkage to ion channel or enzyme
3•cell surface receptors that are enzymes (guanylate cyclase, tyrosine kinase)
4•cytoplasmic/nuclear receptors (DNA-linked)
Role of G-proteins and second messengers in Superfamily 2 receptor-effector coupling
-Receptor changes shape on activation (intrinsic efficacy), regulates G protein> indirectly trasnfers signal to effector (enzyme, ion channel etc) both these -will cause accumulation of difference substance (second messenger) which regulates pathway that causes response
E.G Cyclic AMP B1 ADRENOCEPTOR
cAMP levels increase, effector activated ( protein kinase, phosphorylate protein using atp.adp)
this causes a conformational change and a change in protein activity
(E.G action of phospholipase c-B- lecture 53)
Learning outcomes
Learning Outcomes•Appreciate the need for an activated receptor protein to be linked to a signal transduction process to enable a cellular response to occur.•Distinguish between the different structures and signalling mechanisms associated with each of the four receptor superfamilies, giving relevant examples and clinical applications of drugs targeting each superfamily.•Outline the synthesis and metabolism, intracellular targets and processes regulated by common second messenger pathways.
Role of G-proteins and second messengers in Superfamily 2 receptor-effector coupling
-Receptor changes shape on activation (intrinsic efficacy), regulates G protein> indirectly trasnfers signal to effector (enzyme, ion channel etc) both these -will cause accumulation of difference substance (second messenger) which regulates pathway that causes response
E.G Cyclic AMP B1 ADRENOCEPTOR
cAMP levels increase, effector activated ( protein kinase, phosphorylate protein using atp.adp)
this causes a conformational change and a change in protein activity
Explain the action of Phospholipase c-B
phosphatidyl inositol 4,5, diphosphate (PIP2)
seen in smooth muscle contraction in A1 adrenoceptor
- GQ activates phospholipase cB, PIP2 into DAG and IP3 (2nd messengers)
DAG activates Protein kinase C, phosphorylates proteins e.g of Ca2+ channels, calcium proteins in SR, contractile proteins
IP3 v. water soluble and dissolves into SR ca2+ stores, activates channels to release IntraC calcium store into cytoplasm- both these PROMOTING CONTRACTION
Examples of drugs targeting receptors coupled to adenylate cyclase by G-proteins
- B1 adrenoceptors –Gs-↑cAMP (heart)–agonists are positive inotropic drugs (dobutamine) –cAMP activates protein kinase to phosphorylate proteins leading to ↑ cardiac muscle contraction–antagonists ↓ rate and force of cardiac muscle contraction (atenolol= beta blocker)
- B2 adrenoceptors-Gs-↑ cAMP (airways)–agonists are bronchodilators (salbutamol) –cAMP activates protein kinase to phosphorylate proteins leading to airway smooth muscle relaxation
How is the cyclic AMP response terminated?
cyclic AMP phosphodiesterase >cyclic to linear monophosphate
cannot activate the kinase, cAMP metabolised and return to rest- caffeine inhibits phosphodiesterases
What is the phospholipase c-B signalling pathway?
DAG> Phosphatidic acid (intermediate product)> PIP2 regenerated
IP3> inositol> PIP2 (lithium inhibits this- mood stabiliser)
•dephosphorylate proteins previously phosphorylated by cyclic AMP-dependent protein kinase or protein kinase C (Phosphoprotein phosphatase)
What is superfamily 3?
•Directly linked to tyrosine kinase
- insulin receptor
- insulin-like growth factor receptor
- epidermal growth factor receptor
- (cytokine receptors)
•Directly linked to guanylate cyclase
- natriuretic peptide receptor
- guanylin receptor
Examples of drugs targeting receptors coupled to Phospholipase c-B by G receptors
•A1 adrenoceptors –Gq-↑IP3 /DAG (blood vessels)–agonists are vasoconstrictors (norepinephrine, phenylephrine)
–antagonists are vasodilators (prazosin, doxazosin)
•M3 muscarinic cholinoceptors Gq-↑IP3 /DAG (airway smooth muscle, salivary gland)
–agonists are bronchoconstrictors (acetylcholine) and stimulate saliva secretion (pilocarpine)
–antagonists are bronchodilators (ipratropium bromide)
What is superfamily 3?
•Directly linked to tyrosine kinase -insulin receptor -insulin-like growth factor receptor -epidermal growth factor receptor -(cytokine receptors) •Directly linked to guanylate cyclase -natriuretic peptide receptor -guanylin receptor
Outline the activation and signal transduction mechanisms of T.Kin linked receptors
slide 19 -Activation of receptor proteins causes shape change and promotoes dimerisation, TKin. on L and R phosphorylate one another
SH2 domain recognises phosphorylated receptor and binds to it> enzyme/ transcription factor activation> response
What are the characteristics and some examples of SH-2 domain- containing proteins?
- homologous to src oncogene product
- SH-2 domain contains ~ 100 amino acids
•examples–glucose transporter proteins (GLUT4) responsible for glucose uptake across cell membrane
–MAPK enzyme involved in cell proliferation, differentiation and survival pathways
Give examples of drugs targeting tyrosine kinase-linked receptors
- Treatment of cancers, metabolic and immunological disorders
- renal cancer drug sunitinib–small molecule inhibitor non-selectively targeting ATP binding site on multiple receptor-tyrosine kinases
- breast cancer drug trastuzumab(herceptin)–monoclonal antibody to HER2 receptor-tyrosine kinase’s agonist binding site (receptor regulates cell division/multiplication)
What is the structure of a receptor in superfamily 4?
see slide 30
