CHAPTER 12 PART 1 BIOCHEM SIGNALING GENERAL AND EPINEPHRINE PATHWAY

Signal

this is what binds to a receptor and initates a cellular response

Receptor

this is what receives the signal and activates a cascade of biochemical reactions to result in a cellular response

Examples of signals

cell to cell contact, neurotransmitters, odorants, light, glucose, NO, pressure, growth factors, prostaglandins, microbial pathogens, opioids, pH, hormones are examples of

Response to signal cascades examples

gene transcription, glycolysis, cell growth, cell division/death, stress, mood, firing of action potentials, store fats, gluconeogenesis, produce antibodies, cell migration are examples of

G protein coupled receptor

external ligand (L) binds to receptor (R) activates an intracellular GTP binding protein (G), which regulates an enzyme (Enz) that generates an intracellular second messenger (X) is ___ signaling receptor types

Receptor enzyme (tyrosine kinase)

ligand binding activates tyrosine kinase activity by autophosphorylation ,, which then activates transcription factor which alters transcription

Specificity

ligand binds to a complementary receptor, other ligands do not fit

Sensitivity

receptor has high affinity for the ligand

Amplification

when the number of affected molecules increases geometrically in an enzyme cascade

Modularity

when diverse singaling pathways are formed from interchangeable parts

Densensitization/adaptation

receptor activation triggers a feedback circuit that shuts off the receptor or removes it from the cell surface

Integration

when a cellular outcome is the sum of two signals with opposite or additive effects

Divergence

when a signal activated receptor activates multiple downstream pathways with different cellular outcomes

Localized response

when the components of a signaling pathway are physically tethered together and/or the 2nd messenger is degraded before it can diffuse to different parts of the cell

G protein coupled receptors

GPCR stands for

7

how many transmembrane domains are in GPCRs which are integral membrane proteins

Heterotrimeric

g proteins are _____ meaning they have an alpha, beta and gamma subunit and g proteins bind GTP

Epinephrine

hormone made in adrenal glands (on top of kidneys) and mediates the fight or flight response

Adrenalin

other way to say epinephrine

Broke down, Increase

when epinephrine signals occur glycogen is ______ and there is an _____ in blood glucose levels

Increase

when epinephrine signals occur heart rate and contractility ______

Lipid breakdown

this occurs when epinephrine signals occur and provie an energy source for muscles

Relaxes

when epinephrine signals occur this happens to airway smooth muscles

Beta adrenergic

the receptor for epinephrine

Extracellular

GPCR N terminus is ___

Intracellular

GPCR C terminus is _____

Agonist

increase signal cascade

Antagonist

decrease signal cascade

Isoproterenol

prescribed to treat abnormally slow heartrate (bradycardia)

Bradycardia

abnormally slow heartrate

Propranolol

prescribed to treat high blood pressure, irregular heart rate and migrane and is an example of a beta blocker

G Alpha subunit

when epinephrine binds to the B adrenergic receptor this releases the GDP to promote the binding of GTP to activate the G protein

GDP exchanged for GTP

how is a G protein activated

Adenylyl cyclase

this is the enzyme that is activated by the allosteric activator Galpha protein in the epinephrine signal cascade

cAMP

adenylyl cyclase catalyzes the formation of

peripheral membrane proteins

G proteins are ___ (type of membrane proteins)

cyclic nucleotide phosphodiesterase

this degrades cAMP into AMP

cleave diphosphate and attach the O to the 3’ C on ATP

what forms cAMP

fast lateral diffusion

G proteins being peripheral membrane proteins allows for

Guanine exchange factors (GEFs)

promote the exchange of GDP for GTP in GPCRs

Galpha

this alone is a VERY SLOW GTPase in GPCRs which is why GAPs are required

GTPase Activating proteins (GAPs)

needed to speed up the GTPase activity of G proteins

Rh* (Rhodopsin), Beta-AR*

examples of GEFs (guanine exchange factors)

Protein kinase A (PKA)

cAMP activates ____

PKA

has an AKAP organizer molecular with a dimerization domain that holds 2 inhibitor sequences, each with a compound of a catalysic subunit with a regulatory subunit bound preventing catalytic activity UNTIL cAMP is bound to release the R subunit

Pathways/processes downstream to epinephrine signals

glycogen breakdown, glycolysis, pyruvate oxidation, TAG mobilization and FA oxidation, gluconeogenesis, intracellular Ca2+, synth of dopamine, norepinephrine and epinephrine are …

Turn off cascade

ways to do this to the epinephrine pathway is to remove the ligand, inactivate GPCR, degrade cAMP, hydrolyze GTP by Galpha

Inactivate GPCR

this occurs when the receptor is phosphorylated to create a binding site for arrestin

Arrestin

this is a signal that will turn off the epinephrine pathway even if epinephrine levels are still present

Galpha

this hydrolyzes GTP and rebinds to Gbetagamma to inactivate the epinephrine pathway as adenylyl cyclase is no longer stimulated

PKA

what returns to an auto inhibited state when cAMP is degraded,, and subsequently turns off the epinephrine pathway

Gq

the effector enzyme of this G protein is phospholipase C (PLC)

Gi

inhibitory G protein and will decrease AC activity and therefore decrease cAMP levels

Gs

stimulatory G protein which will increase AC activity and therefore decrease cAMP levels

Lipids

these are the second messengers in Gq GPCR pathways

Vasopressin receptor

the receptor protein in Gi GPCR pathway that decreases PKA activity

Rhodopsin (Rh)

the receptor protein for light in GPCR pathway that activates T (G protein) and decreases cGMP levels and decreases the ligand gated ion channel for Ca2+ and Na+

Phosphodiesterase (PDE)

the effector enzyme in the light/Rh/T GPCR pathway

Odorant receptor (OR)

the receptor protein for odorants in the GPCR pathway that activates Golf and AC to increase cAMP levels to open open a Ca2+ and Na+ ligand gated ion channel

Sweet receptor (SR)

the receptor protein for sweet tastant that activates Ggust and AC and increases both cAMP and PKA levels in order to phosphorylate a K+ ligand gated ion channel

Vasopressin

GPCR pathway that goes VR, Gi, AC, decrease cAMP, decrease PKA

Epinephrine

GPCR pathway that goes Beta AR, Gs, AC, increase cAMP, increase PKA

Light

GPCR pathway that goes Rh, T, PDE, decrease cGMP, decrease internal Ca2+ and Na+

Odorant

GPCR pathway that goes OR, Golf, AC, increase cAMP, increase internal Ca2+ and Na+

Sweet tastant

GPCR pathway that goes SR, Ggust, AC, increase cAMP and PKA, phosphorylates K+ ion channel

Decreases

vasopression _____ cAMP and PKA

Increases

epinephrine _____ cAMP and PKA

Decreases

light ____ cGMP and internal Ca2+ and Na+ levels

Increases

odorants ____ cAMP and internal Ca2+ and Na+

Increases, decreases

Sweet tastants _____ cAMP and PKA and ____ internal K+ levels

Glycogen

the storage form of glucose

AKAP

example of scaffold protein that organizes and localizes the response to the epinephrine pathway, the 5 version of this houses PKA

A kinase anchoring protein 5

AKAP5 stands for

Beta AR K

what is recruited to the GsBY complex with the job of phosphorylating Ser residues on the carboxyl terminus of the receptor to allow binding of Barrestin which initates endocytosis of the receptor-arrestin complex which is the process of desensitizing BetaAR receptors from epinephrine because they no longer have access to extracellular epi

Beta Arrestin (Barr)

what binds to the phosphorylated carboxyl term of B AR receptors

Endocytosis

once Barr has bound itself to the phosphorylated Beta AR what occurs

Dissociates, dephosphorylated

in the endocytic vesicle arrestin _____ and is _______ and returned to the cell surface

Desensitizing Beta adrenergic receptors

the use of BARK and Barr are used to _____