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Flashcards in Molecular pharmacology Deck (46)
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Learning objectives 

  • Introduce the idea of receptor families.
  • Describe how gene cloning and most recently genome sequencing have expanded view of receptor families.
  • Describe some of the better characterized receptor families and list aspects of their structure function activity.
  • Use GPCR adrenergic receptor and nicotinic acetylcholine receptors to detail how current and emerging structures inform on protein conformations that allow receptor function.
  • Describe principles of tyrosine kinases and steroid receptors.
  • Introduce the key principles Pharmacogenomics.
  • Use examples of how genetic determinants effect drugs by changing their Pharmacokinetics and Pharmacodynamics.


When listing the major receptor families, how can you group them by?

  • Molecular characteristics 
  • Major drugs-indicating affinities, efficacies, and relative specificities 
  • Good for revising and drug related write ups 


What are the two classifications of receptor families?

  • Anatomical classification 
  • Pharmacological classification


Are adrenaline and noradrenaline shown to have a wide range of effects?



Whats are the anatomical classifications of drugs?

Different vessels gave distinct response constrict or dilate 


What are some pharmacological classifications of drugs?

  • Ahlquist noted a rank order of potency for adrenergic agonists depending on the nature of the response.
  • Constricting responses: Noradrenalin>adrenalin>isoprenaline  
  • Dilating responses: Isoprenaline>adrenalin> noradrenalin   



Differential pharmacology (structure function) and receptor associated signalling 

  • Known to activate the alpha- and beta-adrenergic beta responses 
  • Build up better idea of underlying receptor
  • - means no response on the drug 
  • Shows to distinct alpha and beta receptors 
  • Propranolol blocks all beta responses 
  • Pindolol only blocks the beta 1 responses 


Tell me about molecular classification and receptor family expansion through gene cloning

  • Identify and sequence the cDNA for the receptor.
  • Predicts the amino acid sequence of the receptor.
  • Repeat for all receptor sub-types compare amino acid to give a molecular classification.
  • Often leads to identification of distinct sub-types not realized by pharmacological classification.


Methods that reveal molecular basis of receptor sub-types 


Tell me about molecular methods that open up diversity in receptor families

  • Hybridise under high temperatures as they are identical much like DNA 
  • Homologous indicate different but related proteins. Would hybridise under lower temperatures


Molecular methods that open up diversity in receptor families


What is genomic DNA made up of and what are each of these components?

  • Genomic DNA is made of DNA sequence
  • DNA sequence is the introns and exons
  •  Exons are part of genomic DNA that go onto make mRNA that encodes the protein
  • Exons come together to make up coding sequence
  • Exons interrupted by introns, would remove and splice introns in order to make proteins 


How can a computer be used for genomic sequencing?

  • Computer can remove introns to get exons. Predict by splicing on computer 

  • Predicted mRNA could look similar would be extinct from those already existing 


What does homology mean?

the state of having the same or similar relation, relative position or structure 


What is cDNA?

cDNA meaning complementary DNA (synthetic DNA in which the sequence of bases is complementary to that of DNA)


How do you build post-genomic receptor families?


How much of the human genome encodes the G-protein coupled receptors?

3-5% of genes 

estimate 30,000 genes in the genome >1000 G-protein receptors 


Tell me about the families in the G-protein receptor super family?

There are 5 families in the G-protein super family, they have 2 different names:

Family 1= rhodopsin family (different names for same thing) 

Family 2= secretin family 

Family 3= Glutamate family 

Family 4= Frizzled/ TAS2 family 

Family 5= adhesion family 


Using family 1 of the G-protein super family as an example, tell me the sub-types of the superfamily

  • Sub types of the super family using family 1 as an example 
  • But a subclassification of the superfamily and all the layers 
  • Alpha 1, alpha 2, beta 1, beta 2, beta 3 (what the starts of the sub-class represent)


Tell me the different effects that adrenaline/ noradrenaline can have an on what receptor they have to act on for this affect 


Tell me about what drugs act on receptors and in what tissues for certain clinical uses...


Tell me about receptor signalling in a cDNA and a mutated cDNA


Whats some useful information for structure function studies?


Tell me about structure function studies?

  • These are used to help understand receptor transduction 
  • 4 ways in which the receptor can be stimulated and the way it can come in via 4 different channels e.g. GPCR, ligand gated ion channels, tyrosine kinases, steroid receptors


What do the G-proteins that associate with GPCRs have?

They are heterotrimeric meaning they have 3 different subunits: alpha, beta and gamma 

alpha and gamma are attached to the plasma membrane by lipid anchors


How does the alpha subunit exchange on G proteins exchange GDP for GTP?

  • When GDP is bound to the alpha subunit, the alpha subunit remains bound to the beta-gamma subunit to form an inactive trimeric protein
  • This conformational change causes the alpha subunit to give up its GDP in exchange for GTP
  •  Once bound to GTP, the alpha subunit dissociates from the beta-gamma complex.


Tell me the primary, secondary, tertiary and quaternary structure of the GPCR?

  • Primary structure: Multifaceted family made up related sub-families (see previous lecture)
  • Secondary structure: all receptors predicted to be seven transmembrane spanning
  • Tertiary structure: Rhodopsin and many structures support the 7 transmembrane model.
  • Quaternary structure: growing evidence that some GPCR may operate as dimers of individual subunits (e.g., Family 3).


Tell me about transduction of GPCRs?

  • Bind agonist supplied from outside
  • Alter receptor conformation
  • Make contact to activate G-protein


Tell me about the secondary structure of an adrenergic GPCR?


Tell me about adrenergic agonist binding sites in transmembrane domains