Signaling Mechs.. Regulating Cell to Cell Communication Flashcards
Goal of creating drugs is to:
- Bind to the receptor or destroy associated proteins
General mech of ion channels. They pass ions:
Down chemical gradient. Ligand bind to receptor and ions flow through
Oligomeric channel:
They bind to another protein. If you mess up one subunit, the channel and protein both suffer.
Gist of Cystic Fibrosis:
CFTR gene = Cl- channel. Disease is AR. Disease = loss of function of this gene. Causes abnormal salt transport across epithelial cell membranes, leading to thick mucus buildup in respiratory epithelial cells.
CFTR ligand:
ATP
What likely happens upon tampering Na+ channel?
paramyotonia, cardiac arrhythmia, epilepsy
Tetrodotoxin:
Na+ channel blocker. Comes from pufferfish. Screws with action potential. Irreversible binding
General gist of Nuclear Steroid Hormone Receptors
Ligand = steroid (hormone), which passes through membrane. Still needs receptor to do job (Act as Transcription factor)
Receptor location in Nuclear Steroid Hormone Receptor:
cytosol or nucleus (usually cytosol)
Steps to Nuclear Steroid Hormone Receptors:
- Hormone passes through membrane. Binds to receptor, causing CHAPERONE to dissociate from receptor.
- Receptor-ligand complex follow nuclear localization sequence (get into nucleus)
- Entire complex binds to hormone receptor element (HRE). Causes gene transcription
Concern with breast cancer and treatment:
- Over expression of estrogen receptors
- Endocrine Therapy works by binding antagonists to estrogen receptor to prevent estrogen from binding.
Tamoxifen = Antagonist (tamoxifen metabolizes to hydroxytamoxifen, which does the actual binding)
General gist of Protein kinase Receptors (PKR)
transmembrane receptor that works by transferring P from high energy molecules (ATP) to target molecules in cytoplasm.
Difference between phosphatase and kinase
Kinase = adds P. PhosphaTase = Takes away P
Protein Kinase Receptor Mech (S/T Kinase)
- ligand binds to EACH ECM (Extracellular membrane (ECM) component.
- Kinase is activated. Phosphorylation chain runs all the way through into cytoplasmic domain.
- Cytoplasmic domain units dimerize now that they are self-phosphorylated
- Cytoplasmic proteins are recruited to it.
Note: Phosphorylation IS reversible (phosphatase)
What interacts with cytoplasmic (“Docking”) component of Protein Kinase Receptors? What additional unit needs to bind in case of Y kinase?
- Grb
2. SH2-Domain, which recognizes phosphorylated Y.
What binds to Grb? What does it do?
- GEF (Guanine nucleotide exchange factor). SoS is an example of this.
- Activates G-proteins like Ras by GEFs switching GDP for GTP
What is a GAP (GTPase Activating Protein)?
Inactivates G-protein by switching GTP for GDP.
What is a G-protein?
It binds GEFs to act as a switch
Why is Ras so important?
Acts as convergence of multiple signal pathways like MAPK
Link Ras to cancer:
Upon mutation, all downstream mutations would be turned on because Sos (a GEF) would be unable to convert GTP to GDP
What’s up with Neurofibromatosisn Type-1?
NF1 gene, which encodes Ras GAP is mutated. Ras is always one since GAP is not able to convert GTP to GDP
What is the deal with Noonan Syndrome?
PTPN11 gene mutation, which is responsible for SHP2. Mutation overactivates Ras
What is the gist of 7-alpha helix receptors?
Most prominent receptor. used for the senses. Ligand binding converts GDP to GTP, activating it.
Sample 7-alpha helix receptor mech (PKA) to release Ca2+ from cytoplasm
- ligand binds, converting GDP to GTP.
- Cytoplasmic domain splits G-alpha from beta-gamma subunit.
3a. Gs-alpha or Gi-alpha triggers adenylate cyclase (AC) - AC converts ATP to cAMP
- cAMP turns on PKA
- PKA releases tone of Ca2+ stored in SER
Sample 7-alpha helix receptor mech (PKC)
- ligand binds, converting GDP to GTP.
- Cytoplasmic domain splits G-alpha from beta-gamma subunit.
3a. Gq-alpha triggers PLC - PLC converts PiP2 to iP3 and DAG
- iP3 cuases Ca2+ release from SER
- DAG binds to C1, Ca2+ binds to C2. PKC is now turned on. Activation is permanent (fact check this)
How does Calmodulin work?
4 Ca2+ inds to it to activate it. Now, it can activate calmodulin activated prtein kinase (CAMK). Mess with CAMKII = Alzheimer’s Disease
