Ion Channel-Linked

Receptors
Multiple subunits that span membrane
Excitatory
nAChR (Na+)
5-HT3 serotonin receptor (Na+, K+)
Glutamate receptors
NMDA receptor (Na+, K+, Ca+)
Kainate receptor
Quisqualate A receptor
AMPA receptor
Inhibitory
GABAa receptor (Cl-)
Glycine receptor (Cl-)

G-Protein-Linked Receptors
Single polypeptide that spans membrane 7 times.
Linked to GTP-binding proteins (G proteins) that
have , , & chain activate events via cAMP or
Ca+ pathway (see below)
mAChR
Adrenergic receptors ()
- uses Ca+ pathway
- uses cAMP pathway
- use cAMP pathway

Dopamine receptors (D1 and D2)

D1 uses cAMP pathway
D2 uses cAMP pathway

Purinergic receptors (A-type and P-type)

mGluR
GABAb receptor
TSH receptor
ACTH receptor
LH receptor
Glucagon receptor
Rhodopsin receptor
Neuropeptide (vasopressin, angiotensin, bradykinin,
opiate, oxytocin, etc.) receptors

Enzyme-linked Receptors
Composed of single or multiple polypeptides that
span membrane once. Cytoplasmic domain has
intrinsic enzyme or associates directly w/ enzyme
Receptor guanylate cyclase ( cGMP activates
cGMP-dep protein kinase/protein kinase G)
ANP receptor
(NO)
Receptor tyrosine kinase (Ras MAP kinase
gene transcription)
All growth factor receptors
Insulin receptor
Tyrosine kinase-associated receptor (Src)
Cytokine receptors
GH receptor
Prolactin receptor
Antigen-specific recptors
Receptory tyrosine phosphatase (CD45)
Receptor serine-threonine kinase (TGFb)

G-Protein linked receptors

1.

cAMP pathway

cAMP levels use stimulatory G (Gs) protein

o
o
o
o
o
o

2.

Signal binds to receptor

Inactive Gs exchanges its GDP for GTP to become active Gs protein
s chain dissociates and stimulates adenylate cyclase to cAMP levels
cAMP activates cAMP-dependent protein kinase (protein kinase A)
Protein kinase A catalyzes phosphorylation of serine and threonine w/in proteins to their activity
Clinical correlation: cholera toxin (catalyzes ADP ribosylation of s) blocks s GTPase activity effects of active Gs protein to continue indefinitely

cAMP levels use inhibitory G (Gi) protein

o
o
o
o

Signal binds to receptor

Inactive Gi protein exchanges its GDP for GTP to become active Gi protein
i chain dissociates and inhibits adenylate cyclase to cAMP levels
Clinical correlation: pertussis toxin (catalyzes ADP ribosylation of i chain) blocks dissociation of i chain thus adenylate cyclase is NOT inhibited)

Ca+ pathway

Signal binds to Gq-linked receptor

Steroid Hormone
(intracellular)
Receptors

Glucocorticoid R
Estrogen R
Progesterone R
Thyroid hormone R
Retinoic acid R
Vit D3 R

Inactive Gq protein exchanges its GDP for GTP to become active Gq protein
Active Gq activates phospholipase C
Phospholipase C cleaves PIP2 into IP3 and DAG
IP3 causes release of Ca+ from ER activates Ca+/calmodulin-dep protein kinase, which phosphorylates serine and threonine w/in proteins to their activity
DAG activates protein kinase C, which catalyzes phosphorylation of serine and threonine w/in proteins to their activity

Proto-Oncogene or AntiOncogene/Tumor-Suppressor)
Ras proto-oncogene (class 3)

Retinoblastoma (RB) anti-oncogene

Chromosome 13

p53 anti-oncogene
Chromosome 17

BRCA 1 anti-oncogene
Chromosome 17

Normal Function

Oncogenic function (i.e. when

mutated, it)

Notes

Encodes G protein that has GTPase activity

G protein attached to cytoplasmic face of
membrane by lipid farnesyl isoprenoid
Activated G protein binds GTP, which
stimulates cell cycle and also splits its own
GTP to terminate stimulation
Normal RB protein binds to gene regulatory
protein (GRP), resulting in no expression of
target genes whose products timulate cell
cycle. Thus cell cycle is suppressed

Encodes an abnormal G protein which

cannot split GTP, thus stimulation of cell
cycle is never terminated

Human bladder, lung, colon, and pancreatic

cancers
Found in ~15% of all human cancers (25%
of lung CAs, 50% of colon CAs, 90% of
pancreatic CAs)

Abnormal RB protein cannot bind to a GRP

expression of target genes thus occurs
resulting in stimulation of cell cycle

Retinoblastoma
Knudson hypothesis: development of
retinoblastoma requires 2 separate mutations
2 types of retinoblastoma:
Hereditary: inherit 1 mutant copy, later
2nd copy is mutated w/in many cells of
retina multiple tumors in both eyes
Nonhereditary: mutation of both copies
occurs w/in 1 cell single tumor
develops in 1 eye

Normal p53 (a zinc finger GRP) causes

expression of target genes whose gene
products suppress cell cycle at stage GI by
inhibiting activity of Cdk2-cycline D and
Cdk2-cyclin E
BRCA protein (a zinc finger GRP) contains
phosphotyrosine and suppresses cell cycle

Mutated protein does not cause expression

of target genes whose products suppress cell
cycle, thus cell cycle is not suppressed

MOST common target for mutation in

human cancers
Associated w/Li-Fraumeni syndrome
Breast and ovarian cancers

COLORECTAL CANCER PROGRESSION

Histopathologic change
Site of Mutation
Normal epithelium to small polyp
Small polyp to large polyp
Large polyp to carcinoma to metastasis

APC anti-oncogene
Ras proto-oncogene
DCC anti-oncogene
p53 anti-oncogene

**NOTE: Hereditary nonpolyposis colorectal CA (HNPCC) does NOT involve mutations of the above genes. It involves a mutation of the HNPCC gene, which is the human homologue
to E. coli mutS and mutL genes. These genes code for DNA repair enzymes. (This is in contrast to most nonhereditary colorectal cancers and familial adenomatous polyposis coli/APC)