Pharm - Receptors Flashcards
How do drugs exert their effects?
- Physiochemical properties e.g. antacids neutralise, sugammadex encapsulates, mannitol affects osmolarity
- Enzymes e.g. ACE-I, neostigmine inhibits acetylcholinesterase
- Ion channels e.g. LAs block fast Na+ channels, CCB block Ca2+ channels
- Receptors e.g. ligand gated ion channels, GPCR, tyrosine kinase receptors, intracellular receptors
(Additional ways if asked)
- Transport systems e.g. digoxin Na/K/ATPase
- Alter hormone production e.g. carbimazole, metformin
- Increase or decrease neurotransmitters e.g. ephedrine, amytriptilline
Define receptor
Proteins with selective ligand binding sites
Define ligand
A substance that binds to a receptor to effect biological changes
The rate of interaction is proportional to the concentration of ligand and the number of receptors. This is called the law of mass action.
What are the different classes of receptor?
- Ligand gated ion channels - direct coupling to open/close a channel. Works in ms. Pentameric e.g. GABA-A, nAChR (N.B nAChR has 2 alpha, 1 beta, 1 gamma, 1 delta)
- MOA: altered ion permeability of cell membrane
- ACh binds to alpha subunits of pentameric nAChR->confomational change->opens central pore->influx of Na+ ions->cell depolarisation
- G-protein coupled - G-protein coupling to influence channel or enzyme. Works in s. e.g. mAChR adrenoceptors
- MOA: Intermediate messengers e.g. cAMP, IP3, DAG, Ca2+
- Tyrosine kinase linked receptor - direct coupling to activate tyrosine kinase. (Receptor has 2 alpha and 2 beta subunits.) Works in mins. e.g. Insulin receptor, growth factor receptors
MOA: ligand binds to alpha subunits causing phosphorylation of intracellular tyrosine kinase on beta subunits
- Intracellular nuclear receptors - couples to intracellular material and effects gene transcription. Works in hrs. e.g. thyroxine receptor, steroid receptor
- MOA: Regulation of gene transcription
- Ligands easily pass through cell membrane->bind to receptors in cytosol->ligand receptor complex enters nucleus->gene transcription and protein synthesis altered.
Tell me more about G-protein coupled receptors
Structure: 7 alpha helices span the membrane. Extracellular component binds to ligand. Intracellular component is coupled to G-proteins which have alpha, beta and gamma subunits.
MOA:
Ligand binds to GPCR which undergoes aconfirmational change and causes GTP to bind to the alpha subunit of the G-protein. This leads to dissociation of the beta/gamma subunit from the alpha subunit/GTP complex. The alpha /GTP complex activates or inhibits enzymes within the cell to influence production of secondary messengers. The alpha subunit has intrinsic GTPase activity and converts GTP to GDP. The alpha/GDP complex is able to reassociate with the beta/gamma subunits, returning to its resting state. It can now reattach to the intracellular portion of the receptor.
Each GPCR can be associated with hundreds of G-proteins.
G-proteins are regulatory proteins which couple activation of surface receptor to activation of an intracellular enzyme. This produces secondary messengers which allows signal transduction and amplification.
Three types: Gs, Gq, Gi
Gs: stimulates adenyl cyclase->rise in cAMP. e.g beta adrenoceptors, glucagon receptors
Gq: stimulates phospholipase C->rise in IP3 and DAG. e.g. alpha1 adrenoceptors, mAChR
Gi: inhibits adenyl cyclase->fall in cAMP. e.g. alpha2 adrenoceptors, opiate receptors
Explain the mechanisms drugs may use to effect positive inotropy?
- GPCR (adrenergic drugs e.g. beta agonists, non-adrenergic drugs e.g. glucagon)
- Reduce breakdown of cAMP e.g. PDE-I
Describe the downstream signalling for Gs, Gq and Gi receptors
Gs
- increase adenyl cyclase-> increase cAMP->activates protein kinase A
Gq
- increase activity of phospholipase C->PIP2 converted to IP3 and DAG->IP3 causes Ca2+ release from ER, DAG activates protein kinase C and so induces the phosphorylation cascade
Gi
- reduces activity of adenyl cyclase->reduction in cAMP
