BIOL 212 Lecture Notes - Lecture 25: Adenylyl Cyclase, Small Gtpase, Molecular Switch
18 May 2018
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Lecture 25 Notes
G Protein-Coupled Receptors (GPCR’s)
- Receptors signal G proteins
- Largest family of cell surface receptors, more than 800 diff GPCR’s in humans
- Used in visual system, olfaction, neurotransmission, many other functions
- Receptors have 7 α-helical transmembrane domains (7TMRs)
o Span membrane 7 times
- Composed of 3 protein subunits α,β,ϒ
Properties of G Proteins
- α and ϒ units tethered to membrane by covalent attachment to lipid group
- α subunit is GTP/GDP binding protein (a molecular switch), binds GDP in inactive state and GTP in
active state
- activation of G proteins by GPCR involved GDP/GTP exchange
- α subunit of G proteins is a small GTPase
- activation of G proteins activates intracellular targets
When G Protein Activated
- target protein activated by activated α subunit, βϒ complex can also activate target proteins
- α switches itself off by hydrolyzing GTP to GDP and phosphate
- can activate enzymes to synthesize small intracellular messenger molecules (second messengers to
amplify the signal)
G Protein-Coupled Receptors Activate Diff Intracellular Signaling Pathways
- ion channels
o activate ion channels in heart muscle cells
- enzyme: adenylyl cyclase (makes cAMP)
- enzyme: phospholipase C
cAMP
- cyclic AMP (cAMP) small intracellular messenger molecule
- rise in cAMP activates PKA (protein kinase A or cyclic-AMP-dependent kinase) which makes a fast
effect of breakdown of glycogen OR PKA activates gene transcription (slow effects)
- allosteric regulator of PKA
Phospholipase C
- activates 2 signaling branches
- inositol phospholipid activated, which activates PKC
G Protein Coupled Receptors Turned off?
- Turn off G proteins (GTP is hydrolyzed to form GDP)
- Turn off receptor
o Rapid dampening: uncoupling from G proteins
o Slower dampening: internalization in endosomes with subsequent: recycling/reactivation OR
degradation by lysosomes and proteasomes (permanent inactivation)
G Protein-Coupled Receptors Imp in Pharmacological Targets
- Over 30% all prescription drugs directed against GPCR’s or their regulatory molecules
- GPCR’s therapeutic targets in many diseases: cancer, cardiac dysfunction, diabetes, central nervous
system disorders, obesity, inflammation, pain
- GRPCR’s good drug targets
o Located on cell surface
o Regulate all aspects cell physiology
o Many “orphan” GPCR’s (w/o a known ligand or function) represent potential for new therapies
find more resources at oneclass.com
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Document Summary
Largest family of cell surface receptors, more than 800 diff gpcr"s in humans. Used in visual system, olfaction, neurotransmission, many other functions. Receptors have 7 -helical transmembrane domains (7tmrs: span membrane 7 times. And units tethered to membrane by covalent attachment to lipid group. Subunit is gtp/gdp binding protein (a molecular switch), binds gdp in inactive state and gtp in active state activation of g proteins by gpcr involved gdp/gtp exchange. Subunit of g proteins is a small gtpase activation of g proteins activates intracellular targets. When g protein activated target protein activated by activated subunit, complex can also activate target proteins. Switches itself off by hydrolyzing gtp to gdp and phosphate can activate enzymes to synthesize small intracellular messenger molecules (second messengers to amplify the signal) Phospholipase c activates 2 signaling branches inositol phospholipid activated, which activates pkc. Turn off g proteins (gtp is hydrolyzed to form gdp)
