Lecture 6: Cell Signaling As A Drug Target

What are the two hallmark features of signal transduction and why are they important

specificity and sensitivity

These two are improtnat becasue they ensure that signals are sent properly and at correct times due to the importance of signals within bioligcal organisms.

How are specitivity and sensitivity acheived within bioloigcal organisms

1) Precise molecular complementarity (specificity)

• a signal and its receptor are perfectly made for one another and only those two (or analogs) go together

2) Some recpeotrs ar eonly in some cells and some signalign molecuels exist in only soem cells. So that the correct thing is doing what it is meant to (sensitityivy.

What kind of bond is created between signaling molecule and receptor & why?

A non-covalent bond, uauslly h-bonding , because they are low in energy cost, easy to create and easy to break, making it so that the signal can be turned on and off with ease.

What is signal transduction

molecules acting as signals, giving way to downstream effects within a cell, like activation and deactivation of pathways

What Are The Eight Features of Cell Signaling

1. Specificity (signal and receptor are made for one another & only analogs can bind)

2. Sensitivity (receptor has a low Kd for its signal)

3. Amplification (signals can amplify effects via enzymatic cascade)

4. Modularity (one signal can have multiple receptors & illicit different effects)

5. Desensitization & Adaptation (negative feedback loop, where attachment of a sigmol results in deactivation of the receptor)

6. Integration (where two signals have opposing effects)

7. Divergence (where a signal can have different effects if the receptor differs)

8. Localized Response (messing up the signal by providing static issues)

What is Kd and what does a high kd mean and what does a low kd mean?

Kd is the affinity of a signaling molecule for a receptor, specifically the concentration of a signal molecule where [half] of the receptor is occupied

• a low Kd means high affinity while a high kd means that there is low affinity

What are the Four General Types fo Signal Transduction? (A ligand/signaling molecule is always here!!)

1. G-Protein Couples Receptors

2. Transcription Change (RPTC)

3. Gates Ion Channel

4. Nuclear Receptor

What is G-Protein Couples Receptor Signaling Transduction

It is where an extracellular signal/ligand binds to a recptor that then activates a G-Protein that regulartes a downstream enzyme which illicits a cellular response

• ligand to g-coupled allows GDP to become GTP then the activated g-protein acts on an enzyme down-stream that illicits a cellular response

What is Transcription Change Cell Signaling (recprotor, phospho, transcirpion change)

A kind of cell signaling that has a receptor enzyme (has its own enzymatic activity) that then activates TYROSINE KINASE via phosphorylation and that activates a transcription factor

• think p53

What is gated ion channel cell signaling

• a ligand is necessary for an ion-channel to open. if the ligand is not there only membrane potential can open it

What is Nuclear Receptor Cell Signaling

Where a HOROMONE (the signaling molecule) binds to a recpeotr and illicit gene expression changes/regualtion

What are Adrenergic Receptors

Adrenergic receptors are that SPECIFICALLY bind to agonists and antagonists, creating down-stream effects

How are adrenergic recptors differentiated (two things)

their affinity and responses to specific agonists and antagonists

What are the four types of adrenergic receptors

the four types of adrenegric receptors are A1, A2, B1 & B2.

What are agonists

Agonists are signaling molecules (and their analogs) that bind to their adrenergic receptor and illicit an “activating” response on a cellular pathway

Remember: that their (antagonists and agonists) analogs work too

their analogs work too.

True or False: Agonist always illicit a activating response and Antagonists always illicit a negative response

False; usually is the better word here, but the response is not always anything.

What are antagonists

antagonists are signalign molecules (and their analogs) that bind to their receptor and illicit a deactivating response to a cellular pathway.

How do antagonist work to usually illicit a deactivating response in a cellular pathway

an antagonist work by binding to a receptor that has its own agonist (activator) and blockign said agonist from binding.

• BLOCKING THE AGONIST FROM BINDING

Summarize the epinephrine cell signaling pathway.

1. Epinephrine binds to its recptor which is a G-Couples Protein

2. Epenephrine bindign allows GDP to become GTP, dislowding Gsa from the GSabg complex.

3. GSa leaves and goes on to activate adenyly cyclase

4. Adenyl cyclase acitvates cAMP

5. cAMP activates PKA

6. PKA goes on a phosphorylation cascade, attacking Ser or Thr illiciting

7. the organism’s fight or flight .

What is epinephrine

the signaling molecule in the epinephrine cell signaling pathway

What is the end product of the epinephrine cell signaling pathway

an organism’s fight or flight

what is the G-protein complex in the epinephrine cell signaling pathway and what are the components

The g-protein complex is the receptor. It is made up of three parts

1. Gsa

2. Gsb

3. Gsg

Gsa has its GDP turned into GDP and then goes on to activate adenyl cyclase

What is cAMP

cAMP is a cyclic nucelotide phosphodiesterase and is activate dby andyly cyclase and goes on to activate PKA

What is PKA

PKA is in the epinephrine cell signaling pathway and is a protein kinase activated by cAMP. It phosphorylates proteins at their Ser and Thr.

What are the mechanisms of control for the epinephrine cellular pathway

1. EP has a short half life

2. cAMP is degraded

3. GSa can be dephosphorylated, deactivating adenyly cyclase

What is isoproternol (ISO ISO, IM ON ONE)

an agonist of the epinephrine pathway, that B1 and B2 receptors, increasing cAMP level and PKA activity.

• increasing cardiac output and vasodilatation

What do B1 and B2 receptors control

• B1 has to do with the heart and cardiac output,

• B2 has to do with muscles, blood vessels, and airway

What is Proponolol (no, lol)

it is an antagonist in the epinephrine cell pathway, that binds to B1 and B2 receptor.

What is Cholera Toxin?

Cholera toxin is a protein that is released by the cholera bacteria and binds to GM1 integral protein

What does cholera toxin bind to and what is the DIRECT product of this binding?

the toxin, cholera protein binds to GM1 receptor in enterocytes of intestinal cells and activates Gsa

What happens when Gsa is activated by the GM1 binding to Cholera Toxin

What happens is that Gsa activates Adnylyl Cyclase adn then activates cAMP, then cAMP upregulates CTFR

What happens to CTFR when Cholera Toxin is there?

CTFR is enhanced causing dramatic efflux of ions and water from the infected cells, leading to water excretion, diarrhea and dehydration. (H2O and Cl-)

What is PKA and can it be inhibited?

Protein Kinase Activator that phosphorylates proteins and it is vital for cell function. So it cannot be inhbited

What is balanol?

balanol is a natural fungal metabolite that is a competitive ATP-inhibitor of PKA and PKC

WHat is crizotnib

off-target affector of PKA