Lesson 17: GPCR and RTK Signaling

adenylyl cyclase

membrane-bound enzyme that catalyzes cyclization of ATP --> cAMP

cAMP

cyclic AMP

PKA

protein kinase A

results of PKA activation (3)

turns off glycogen synthesis, stimulates glycogen breakdown, stimulates gluconeogenesis

signaling helix on G𝛼

Gβγ binding site when inactive; when GTP binds, signaling helix changes shape & dissociates from βγ; signaling helix also binds adenylyl cyclase

β2 adrenergic receptor

7TM GPCR that binds epinephrine --> energy production

RSG2

GAP protein that stimulates GTPase activity of G𝛼

βARK

β arrestin kinase; binds to Gβγ and phosphorylates cytoplasmic tail of 7TM

β-arrestin

binds to phosphorylated tail of 7TM, tagging it for endocytosis

cAMP PDE

cAMP phosphodiesterase; breaks cAMP down into 5'-AMP

rods vs cones

rods = low light, black and white; cones = color vision

cGMP gated ion channel

sensitive to [cGMP], open at rest; selective for Na+ and Ca2+

rhodopsin

7TM light receptor

transducin

heterotrimeric G-protein associated with/ rhodopsin

retinal

chromophore in rhodopsin; sensitive to light

effect of light on retinal

changes from 11-cis-retinal to 11-trans-retinal

cGMP PDE

cGMP phosphodiesterase; breaks cGMP down into GMP

guanylyl cyclase

catalyzes GTP --> cGMP

rhodopsin kinase

phosphorylates tail of trans-rhodopsin

arrestin

binds to phosphorylated tail of trans-rhodopsin, inactivating it

PLC

phospholipase C; produces IP3

enzyme linked receptor

ligand-activated enzyme

𝛼-subunit of enzyme linked receptor

extracellular ligand binding domain

β-subunit of enzyme linked receptor

connects 𝛼 to membrane

C-terminus of enzyme linked receptor β-subunit

tyrosine kinase

tyrosine kinase

phosphorylate Tyr residues by hydrolyzing ATP

insulin

peptide hormone released in response to high glucose; stimulates glycogen synthesis, glycolysis, and cell division

Shc protein (insulin pathway)

stimulates gene expression and cell division

IRS (insulin pathway)

stimulates glucose uptake and glycogen synthesis

SH2 domain binds to pTyr

SH3 domain binds to Pro-rich regions on PI-3K

activation loop of RTKs

3 Tyr in β-subunit; inactive until phosphorylated

adaptor protein

proteins w/ no enzymatic activity that bind to pTyr

PI-3K

phosphoinositide-3-kinase; phosphorylates PIP2 --> PIP3

PTB domain

pTyr binding domain found on Shc and IRS

SH2 domain

binds to pTyr adjacent to Asn

PDK1

PIP3 dependent kinase

Akt

protein kinase B

serine phosphatases (insulin pathway)

dephosphorylate Akt

PTEN

lipid phosphatase; dephosphorylates PIP3 --> PIP2

tyrosine phosphatases

depohosphorylates pTyr

epidermal growth factor

peptide hormone that stimulates cell division

GRB2

growth factor receptor bound 2; SH2 domain binds to pTyr; SH3 domain binds SOS

SOS

son of sevenless; proline-rich regions bind to SOS; binds to and activates Ras

activation of EGF receptors

EGF binds to 2 separate monomers, stimulating dimerization then autophosphorylatuon

Ras

anchored monomeric G-protein like G𝛼 that causes MAP kinase signaling cascade by binding to Raf

EGF kinase cascade

Ras --> Raf --> MEK --> ERK

Raf

held at membrane by Ras so it can be phosphorylated by SRC; phosphorylates MEK

MAP

mitogen activating protein; stimulate mitogens which stimulate mitosis

MEK

MAP ERK kinase; activates ERK

ERK

extracellular related kinase; when activated, it dimerizes, enters nucleus, and phosphorylates transcription factors that stimulate cell division

Ras GAP

inactivates Ras by hydrolyzing GTP --> GDP

which pathways use GTP/cGMP as a messenger vs ATP/cAMP

GTP: rhodopsin; ATP: epinephrine, olfaction