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Biology 2382B Lecture Notes - Rapgef3, Priapism, Vasodilation

Course Code
BIOL 2382B
Jessica Kelly

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Lecture 16 GPCR Functions
G protein-coupled receptors (GPCRs) are a large family of integral membrane proteins that respond to a
variety of extracellular stimuli. Each GPCR binds to and is activated by a specific ligand stimulus that
ranges in size from small molecule catecholamines, lipids, or neurotransmitters to large protein hormones.
When a GPCR is activated by its extracellular ligand, a conformational change is induced in the receptor
that is transmitted to an attached intracellular heterotrimeric G protein complex. The Gs alpha subunit of the
stimulated G protein complex exchanges GDP for GTP and is released from the complex.
In a cAMP-dependent pathway, the activated Gs alpha subunit binds to and activates an enzyme called
adenylyl cyclase, which, in turn, catalyzes the conversion of ATP into cyclic adenosine monophosphate
(cAMP).[2] Increases in concentration of the second messenger cAMP may lead to the activation of
cyclic nucleotide-gated ion channels[3]
exchange proteins activated by cAMP (EPAC)[4] such as RAPGEF3
an enzyme called protein kinase A (PKA).[5]
The PKA enzyme is also known as cAMP-dependent enzyme because it gets activated only if cAMP is
present. Once PKA is activated, it phosphorylates a number of other proteins including:[6]
enzymes that convert glycogen into glucose
enzymes that promote muscle contraction in the heart leading to an increase in heart rate
transcription factors, which regulate gene expression
Specificity of signaling between a GPCR and its ultimate molecular target through a cAMP-dependent
pathway may be achieved through formation of a multiprotein complex that includes the GPCR, adenylyl
cyclase, and the effector protein.[7]
Regulation of Adenylyl Cyclase (effector)
Adenylyl cyclase catalyzes formation of cyclic AMP (cAMP) …
GPCR/cAMP pathway is very common in many mammalian cells
GPCR can bind to both inhibitory and stimulatory ligands

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Bound GPCR interact with G proteins whose G
subunits may be inhibitory or
stimulatory to the effector protein
Gs stimulates adenylyl cyclase to produce cAMP
Gi inhibits adenylyl cyclase hindering the production of cAMP
Inappropriate Activation of Adenylyl Cyclase Cholera Toxin
Bacteria V. cholera produce cholera toxin (a peptide)
Toxin that accumulates in the intestinal lumen binds to receptors on the apical
surface of intestinal epithelial cells and is transported into the cell by retrograde
Once inside the cell the toxin binds to the G
s subunit which binds GTP but
cannot hydrolyze it (G
s is always active)
Constitutively active (toxin bound) G
s-GTP has strong association with adenylyl
cyclase causing it to constitutively produce cAMP
High Intracellular cAMP levels activate CFTR to pump Cl- ions into the intestinal
Na+ ions follow Cl- ions as well H2O will follow by osmosis

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Thus through this mechanism cholera toxin leads to massive water loss and
dehydration that can if not treated (by replenishment of water with electrolyte
solution) can lead to death
**CFTR mutation that causes CF** recessive allele thought to have propagated in
white Europeans due to heterozygote advantage that came from having mutation
individuals that are heterozygous do not lose as much water when infected with
cholera thus less likely to die from infection
Inappropriate Activation of Adenylyl Cyclase
Whooping Cough (Pertussis Toxin)
Bordetella pertussis toxin enters ciliated epithelial cells in lungs
Pertussis toxin maintains G
i in inactive state (GDP) (i.e. inhibits G
Inactive state of inhibitory G
subunit results in increase in adenylyl cyclase activity =
higher levels of intracellular cAMP…
Increased levels of cAMP = Increased CFTR activity = Increased pumping of Cl- out
of lung epithelia cells (Na+ follows
so does H20 by osmosis)…
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