Molecule Mechanisms of the G-Protein Coupled Receptors

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Types of receptors
G Protein-Coupled; Ligand-Gated Ion; Enzyme-Coupled; Nuclear
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G Protein-Coupled Receptor
7 transmembrane domains, detect molecules outside the cell, activate internal signal transduction pathways. Make up 50% of current drug targets e.g Atenolol.
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Class A Rhodopsin-Like
Short N terminus, agonists bind with extracellular loops and transmembrane domain e.g. histamine receptors.
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Class B Secretin-Like
Larger globular N-terminus. No small molecule drugs on market. E.g. calcitonin receptors.
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Class C Metabotropic Glutamate/Pheromone
Metabotropic glutamate receptors, very large N-terminal domain, form obligatory dimers. Few small molecule drugs on market. E.g. GABAb receptors.
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Class D
Fungal pheromone
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Class E
cAMP receptors
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Class F
Fizzled/ Smoothened
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GPCRs Activation
Binding of a signaling molecule to a GPCR results in G protein activation, which in turn triggers the production of any number of second messengers.
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Salbutamol
Opens up the medium and large airways on the lungs, used to treat asthma.
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Sumatriptan
Used to treat migraine headaches. Features an N-methyl sulfonamidomethly group at position C-5 on the indole ring.
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Pilocarpine
Used to treat increased pressue inside the eye and dry mouth, constriction of the pupil following dilation.
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Desensitization of GPCRs
Prevents continuous activation of GPCRs
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Homologous Desensitization
Restricted to agonists through specific receptor
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Heterogeneous Desensitization
Affect receptors that share a component of the same cascade.
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Distinct From Downregulation
Reduction in the numbers of a functional receptor.
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Internalization and Desensitization of GPCRs
Receptors are feedback phosphorykated by GRKs and PKA in rapid desensitization due to G protein uncoupling. Further promoted by the binding of arrestins to phosphorylated agonist-activated GPCRs.
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Imaging of b-arrestin Translocation
BRET sensors monitor GPCRs and b-arrestin trafficking. Anchoring rGFP at the plasma membrane or endosomes to generate high dynamic spectromteric BRET signals on the ligand-promoted recruitment.
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Tolerance
Progressive reduction in the effectiveness of a drug, not specific and hard to resolve.
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Enkephalin
Pentapeptide involved in regulating nociception in the body, internally derived and bind to the body's opiod receptors. Met-enkephalin and Leu-enkephalin are both products of proenkephalin gene.
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Morphine
Prototypical opioid, interacts prodominatly with the y-g opioid, discretely distributed in the human brain. Found on terminal axons of primary afferents within laminae I and II of the spinal cord and spinal nucleus.
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Functional Selectivity
Ligand-dependent selectivity for certain signal transduction.
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Signalling Affects Trafficking of GPCR
Deeply conserved signalling mechanism, e.g adenylyl cyclase is an enzyme with key regulatory roles in essentially all cells.
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Adenylyl Cyclase
regulated by G proteins. Adenylyl cyclase activity is controlled by G proteins. The inactive or inhibitory form exists. Conformational change causes the alpha subunit to dissociate from the complex and become bound to GTP
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Tolerance of Opioids
Treat pain, analgesic tolerance coupled with development side effects of respiratory depression. Now developing semisynthetic morphine alternatives, bind to the same y-opioid receptors to produce the same results.
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Other cards in this set

Card 2

Front

7 transmembrane domains, detect molecules outside the cell, activate internal signal transduction pathways. Make up 50% of current drug targets e.g Atenolol.

Back

G Protein-Coupled Receptor

Card 3

Front

Short N terminus, agonists bind with extracellular loops and transmembrane domain e.g. histamine receptors.

Back

Preview of the back of card 3

Card 4

Front

Larger globular N-terminus. No small molecule drugs on market. E.g. calcitonin receptors.

Back

Preview of the back of card 4

Card 5

Front

Metabotropic glutamate receptors, very large N-terminal domain, form obligatory dimers. Few small molecule drugs on market. E.g. GABAb receptors.

Back

Preview of the back of card 5
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