Receptors and Cell Signaling Flashcards
effectors in cell signaling: what do they do
alter the activity of different components downstream and generate secondary messengers that elicit a particular cellular response (enzyme activity, gene expression, etc)
how are signals terminated in cell signaling
removal of the signaling molecule and/or receptor or attenuation/inactivation of the signaling events
endocrine signaling
- what is the signal
- long distance/short distance
- long term/short term
- hormone (ex: epinephrine)
- long-distance signaling
- short term signaling (half life is on minute scale)
paracrine signaling
- long distance/short distance
- long term/short term
signal diffuses to neighboring target cell
ex: testosterone
- local signaling
- short lived signals
how testosterone signaling works
leydig cells synthesize and secrete testosterone which induces spermatogenesis by acting on sertoli and germ cells
autocrine signaling
secreting cells express surface receptors for the signal; or release to cells of the same type
ex: interleukin-1 promotes its own replication in immune response
ex: growth factors in cancer cells
direct/juxtacrine signaling
signal binds to signaling cell which then binds to receptor on the target cell; acts like a bridge between the two cells
ex: heparin-binding epidermal growth factor
ex: immune cells
hydrophilic signaling
- how it works with plasma membrane
- examples
- receptors involved
cannot penetrate the plasma membrane, the receptor has to be on the membrane; signaling molecule-receptor complex initiates the production of a second messenger molecule in the cell
epinephrine, insulin, glucagon
GPCRs and RTKs
lipophilic signaling
- how it works with plasma membrane
- examples
signals can pass though the membrane of the target cell; ligand binds to receptor protein inside the cell (cytosol or nucleus)
steroid hormones, thyroid hormones, retinoids
where can receptors be located for lipophilic signaling
nucleus or cytosol
cytoplasmic receptors in lipophilic signaling
exist in inactive complex with HSP90; when they bind to ligand HSP dissociates and the hormone receptor complex translocates to the nucleus where it binds to the HRE in the promoter region of specific genes
hormone response element
specific DNA sequence in the promotor region of specific genes; binds to hormone receptor complex in cytoplasmic lipophilic signaling
nuclear receptors in lipophilic signaling
exists in the nucleus already bound to DNA; ligand will activate the complex to regulate the transcription of specific genes
nAChR
GABAa
5-HT3
GlyR
what do these have in common
ligand gated ion channels
G protein coupled receptors (GPCRs) signaling
- 4 steps
ligand binds to extracellular domain –> conformational changes in the GPCR
intracellular domain activates its G protein and GDP –> GTP
GTP bound G protein interacts with membrane bound effector protein –> secondary messenger
how is GPCR signaling terminated (3 ways)
- dissociation of signaling molecule
- inactivation of the G protein
- reduction of concentration of secondary messenger
guanine exchange factor (GEF)
activates GPCR by adding a phosphate to the inactive GDP bound GPCR; GDP becomes GTP and the alpha subunit dissociates
GTPase-activating protein (GAP)
accelerates the hydrolyzation of GTP into GDP, inactivating GPCR
Gs type GPCR signaling
stimulates adenylate cyclase which activates cAMP –> activates PKA –> phosphorylates target proteins to alter their activity
- ex: epinephrine when it binds to the beta-adrenergic receptor
- ex: histamine
Gt type CPCR signaling
activated by light; stimulates cGMP phosphodiesterase –> cleaves cGMP into 5’-GMP
type of negative signaling (the signal is on in the absence of light)
Gi type GPCR signaling
inhibits adenylate cyclase; cAMP is not produced and PKA is not activated
- ex: epinephrine when it binds to the alpha-adrenergic receptor
- ex: dopmamine
Gq type GPCR signaling
two end points
activates phospholipase C; breaks PIB2 into DAG and IP3
DAG –> PKC –> phosphorylation of target proteins to alter their activities
IP3 –> goes to the ER to open channels to release Ca2+ into the cytosol (calcium is the secondary signal) –> activation of Ca2+/calmodulin-dependent proteins
ex: acetylcholine
what happens when epinephrine is bound to beta-adrenergic receptors
relaxation of bronchial and intestinal smooth muscle
can be used to relieve bronchospasms during asthma attack
what happens when epinephrine binds to beta adrenergic receptor in the heart
causes contractions
can be used to restore cardiac rhythms after MI
cAMP phosphodiesterase
hydrolyzes cAMP to AMP
cGMP phosphodiesterase
hydrolyzes cGMP to 5’GMP
how does viagra work
inhibits cGMP PDE which increases the concentration of cellular cGMP, leading to smooth muscle relaxation and vasodilation
how does caffeine lead to increased heart rate
it inhibits cAMP PDE
how does nitric oxide lower blood pressure
NO is produced in epithelial cells; diffuses to neighboring muscle and activates guanylate cyclase –> production of cGMP –> smooth muscle relaxation and vasodilation
how does the cholera toxin work
covalent modification of alpha subunits ADP causes ribosylation of arginine –> decreases GTPase activity –> Gs remains active and continues to stimulate adenylate cyclase which causes overproduction of cAMP –> open Cl- channels in intestinal cells –> loss of electrolytes and water and increased diarrhea
how does pertussis work
ADP ribosylation of cystine on Gi prevents activation and dissociation of alpha subunit from the G protein complex –> less inhibition of AC and overproduction of cAMP –> loss of fluids and excessive mucous in airway epithelial cells
mechanism of water secretion in cholera
toxin activates AC to produce cAMP
leads to secretion of Cl-
causes build up of negative potential across the membrane –> secretion of Na+ –> net secretion of NaCl
NaCl builds up an osmotic gradient across membrane –> water secretion
4 types of signal desensitization
- hormone levels drop, causing decreased adenylate cylase activity, decreased cAMP, and decreased PKA activity
- phosphodiesterases removing cAMP/cGMP
- receptor sequestration in endosome
- receptor destruction in endosomes and lysosomes
G protein receptor kinase (GRKs)
phosphorylate the GPCRs
- arrestin binds to the 3rd intracellular loop and prevent G-alpha from interacting with third loop; GDP does not get converted to GTP to activate GPCR
3 part of receptor tyrosine kinase (RTK)
- extracellular domain which binds the ligand/signaling molecule
- single alpha helical transmembrane domain
- an intracellular domain with tyrosine kinase activity
receptor tyrosine kinase (RTK) signaling
- 4 steps
- ligand binds to ECD causing dimerization
- specific tyrosines are phosphorylated
- phophotyrosine is recognized and bound by adapter and docking proteins (SH2 domain of Grb2) –» either RAS dependent or RAS independent pathway
- triggers phosphorylation of protein targets in nucleus, plasma membrane, cytoplasm
–> alteration in gene transcription and protein acitvity
what is RAS-dependent signaling facilitated by
mitogen-activated protein kinase family
MAPK
GRB-2
adaptor protein; SH2 is a domain of GRB-2; recognizes and binds to motifs on the receptor that contains phosphorylated tyrosine in RTK signaling
how is RTK signaling terminated
- degradation of signaling molecules
- ligand induced endocytosis followed by lysosome degradation
- accelerated RAS inactivation
- dephosphorylation
what do point mutations in RAS cause
lung, colon, and pancreatic cancers
how do mutations in RAS cause neurofibromatosis
characterized by an inactivating mutation in neurofibromin (NF-1) gene, which normally encodes a GAP for RAS
RAS uncontrollably activated pathway for nerve tissue growth –> optical glioma, macrocephaly, learning disabilities, Lisch
what do point mutations in RAS cause
30%-50% of lung and colon and 90% of pancreatic cancers
