Molecular Signaling Flashcards
endocrine
signal transported in blood long-distance, long-lasting, freely diffuses
paracrine
signal diffuses to neighboring target cell of a different cell type, local signaling, short lived
autocrine
secreting cells express surface receptors for the signal
ex. interleukin 1, release to cells of same type or near by, common in chemokines
direct/juxtacrine
bind to signaling cell which then binds to receptor on the target cell
ex: heparin binding to epidermal growth factor
hydrophilic signaling
do not penetrate plasma membrane but interact with specific receptors at cell surface
examples of hydrophilic signaling
epinephrine, insulin, glucagon
signaling molecule for hydrophilic signaling
receptor complex initiates production of second messenger molecules insude cells
trigger downstream cellular repsonses
receptors involved in hydrophilic signaling
G protein-coupled receptors
receptor tyrosine kinase
lipophilic signals pass through the
plasma membrane of target cells
ex. steroid, thyroid, retinoids
bind to specific receptor proteins inside the cell
the signaling molecule for lipophilic signaling is
receptor complex that acts as a transcription factor
cytoplasmic receptors
inactive form complexed with HSP 90
hormone receptro complex translocates to nucleus where it binds to specific DNA sequence called hormone response element
nucleear receptors
already present in nucleus bound to DNa
the homrone allows for interactions with additional proteins and activate the complex
both cytoplasmic and nuclear receptors regulate
transcription of specific genes
long half lives (hours to days)
GPCR
structural motif
extracellular domain for signaling
transmembrane domain with 7 a-helices
intracellular domain-interacts with g proteins
GPCR signaling
trimer G protein with three subunits (aBy)
ligand binds receptor
conformational change
GPCR interacts with G protein
Receptor then acts as GEF-guanine exchange factors
inactive G protein has GDP, to be active, must exchange it for GTP
GTP-a separates from By and activates or inhibits effector molecule
effector molecule catalyzes reactions that produce secondary molecules
intrinsic GTPase activity of the G protein hydrolzes GTP to GDP to inactivate the G protein again
activation accelerated by GTPase ativating protein (GAP)
signal desensitization by
drop in hormone levels
decrease in adenylylyl cyclase-decreases cAMP-decreases PKA
signal desensitization by
phosphodiesterase removinh cAMP/cGMP
signal desensitiization by receptor sequestration and preceptor destruction
either by endosomes or endosomes and lysosomes as proteases
Gs stimulates
adenylate cyclase
Gt stimulates
stimulates cGMP phosphodiesterase
Gi inhibits
adenylate cyclase
Gq activates
phospholipase C
GPCR with signaling via Gq, PLC, PKC (fig 7.5) and
book
hydrolysis of cyclic nucleotides
enzymes hydrolyze cyclic nucletoides to regulate their cellular levels
cAMP phosphodiesterase hydrolyzes cAMP to AMP
- cGMP phosphodiesterase: hydrolyzes cGMP to 5’GMP*
- inhibitors of cGMP PDE increase concentration of cellular cGMP and prolongs its effects for a greater amount of time leading to smooth muscle relaxation and vasodilation resulting in erection (viagra, cialis)*
caffiene inhibits PDE leading to accumulation of cAMP, increasing heart rate
inhibition of G proteins by bacterial toxins: Cholera
cholera toxin prevents the inactivation of Gsa
cholera illness by consumption of contaminated water
- covalent modification of a subunit of Gs*
- ADP ribosylation of Arg in Gs a decreases intrinsic GTPase activity*
- Gsa remains active GTP bound form and continuously stimulates adenylate cyclase, resulting in overproduction of cAMP*
Overabundance of cAMP in intestince causes
cell opens Cl channles and loss of water and electrolytes happens
cAMP activates the CFTR and secretes the Cl which leads to water secretion
inhibition of G proteins by bacterial toxins: Pertussis
- Pertussis toxin prevents the activation of Gia ADP ribosylation of Cys on Gia prevents actication and dissociation of a subunit from teh trimeric G protein complex*
- Less inhibition of AC and hence overproduction of cAMP*
in airway, pertussis causes loss of fluids and mucous secretion increase presents as whooping cough
nitric oxide diffuses to
neighboring muscle and activates guanylate cyclase, leading to production of cGMP
cGMP produced from activated guanylate cyclase resulting in smooth muscle relaxation and vasodilation
NTG and other nitrates decompose to form NO and help lower BP
should not take cGMP PDE inhibitors (erectile dysfunction drugs) with NO because it can cause extreme vasodilation and fatal BP drop
histamine and antihistamine
histamines are made from histidine which is a ligand that binds to four histamine GPCRs
antihistamines are lipophilic compounds that block the effects of histamine to the H1 GPCR
RTK motif
extracellular domain with signaling molecules
single helix
intracellular domain posses tyrosine kinase activity
RTK signaling
signal binds to ECD inducing a conformational change
tyrosine is autophosphorylated
phosphotyrosine recognized by adapter and docking p (SH2 domain of grb2)
triggers phosphorylation of protein targets leading to alteration in gene transcription and protein activity
-this is either ras dependent or ras independent
RTK signaling is terminated by several ways (degradation, endocytosis, lysosomal degradation, accelerated ras inactivation, dephosphorylation
ras dependent signaling
facilitated by mitogen activated protein kinase (MAPK) faily
ras independent singaling
facilitated by a different kinase (NOT MAPK)
many signaling molecules are
protooncogenes that can mutate into oncogenes
Monomeric G proteins
small g protein part of RAS familt
very differnt from the trimeric G proteins in GPCR
monomeric G proteins have a single polypeptide chain
control a diverse process: cell proliferation, intracellular vesicular traffic, survival, apoptosis, shape, transport
have intrinsic GTPase activity, mutations here can cause cancer
include RAS, RAB, RHO, RAN
RTKs in cancer
excessive signaling from mutated/overexpressed RTKs associated with cacner
RTKs are the target of pharm. inhibitors
breast cancer drug herceptin targets HER2 in the EGF-binding RTKs
Ras in cancer
mutant forms of ras or GEFs or GAPs implicated in many cancers
half of lung and colon and 90% of pancreatic cacners associated with activating point mutations in RAS
mutations decrease GTPase activity and lock it in active GTP-bound state
ex. neurofibromatisis caused by inactivating mutation in NF-1 gene which encodes GAP for RAS. here RAS uncontrollably activated pathways for nerve tissue growth
