Term
| In preclinical phase, drugs are look at for properties that put them into which categories? |
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Definition
Teratogen: adverse effects in fetus
Mutagen: inberitable disease
Carcinogen: cancer causing |
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Term
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Definition
| drugs and their composition, uses, and effects on living systems. |
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Term
| Pharmacokinetics? Pharmacodynamics? |
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Definition
-What the body does to the drug
ex. drug absorption, distribution, metabolism, and excretion
-What the drug does to body.
biochemcial and phsyiological effects of drugs and the MOAs |
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Term
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Definition
| combo of pharmcokinetic and pharmacodynamics to the therapueutic management of patients |
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Term
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Definition
| use of drugs in treatment and prevention of disease |
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Term
| Characteristics of Drug Action |
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Definition
-most drugs are reversible
-magnitude/frequency = fxn of drug concentration
-Graded response = ranked/scaled
There are a few exceptions: quantal response (all or nothing) in seizure and antiarrhythmic |
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Term
| Therapeutic window/concentration range |
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Definition
| the concentration range between the minimal effective concentration that will result in a pharmacological desired outcome and the minimum concentration that results in unacceptable toxicity |
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Term
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Definition
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Term
| Receptors can encompass... |
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Definition
-Coupled to signal transduction mechansim
-enzymes
-transport and structural proteins
-ion channels
-dna and rna... |
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Term
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Definition
| exo or endogenous substances such as hormones that bind to receptor proteins to cause signaling events. |
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Term
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Definition
| everything that occurs between binding of ligand to receptor and the effect |
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Term
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Definition
-Pharmacologic: Mediator they respond to
-Biochemical: the response elicted
-Molecular/Structural: primary amino acid sequence |
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Term
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Definition
| Ligand Gated Ion > G Protein Coupled Receptors > Kinase-Linked > Nuclear |
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Term
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Definition
| Pharmacologic vs Physiologic |
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Term
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Definition
*Remember not a G-protein
1)Monomeric protein
2) 7 transmembrane alpha-helical segments
3) C-terminal tail (regulatory) |
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Term
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Definition
I) Rhodopsin
II) Secretin-like
III) Metabotropic glutamate |
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Term
| Role of Effector Molecules |
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Definition
| Synthesis of 2nd Messengers |
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Term
| Activation of GPCR leads to? |
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Definition
| Activate trimeric G-proteins which then affect EFFECTOR molecules |
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Term
| Important Second Messengers |
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Definition
cAMP, cGMP,
PI (phospho-inositides)
AA (arachdonic Acid), DAG,
Sphigolipids (ceramide)
Ca, NO |
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Term
GPCR: Heterotrimeric:
What is basal inactive state? Active? |
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Definition
Basal State -alpha:beta:gamma complex with GDP bound on the Alpha.
Active State - Exchange GTP and GDP, so now have two Active Proteins 1)alpha-GTP and beta:gamma |
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Term
| What is unique about alpha? |
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Definition
It has "intrinsic GTPase activity" which means hydrolyzes the GTP naturally so it can go back to GDP basal state.
*but this "hydrolysis" is slow...so remiains active for a while |
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Term
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Definition
Cholera: Modifies alpha by adding ADP-Ribosyl = Inactivate GTPase = permanant active = high cAMP...
-Pertussis: inactivates alpha = increased cAMP |
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Term
| Do GPCR's exist as single proteins? |
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Definition
| Not only single, but also dimers and oligomers such as homomer and heteromers. |
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Term
| Which 2nd messengers are intracellular? Extracellular? |
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Definition
-cAMP, cGMP, Inositol TriP (IP3), DAG and Ca
- NO, Eicosanoids |
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Term
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Definition
| Synthesized from Adenylyl Cyclase: 2 catalytic domains and 12 Transmembrane |
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Term
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Definition
cAMP stimulates PKA (cAPK), which is a heterotetramer of 2R and 2C subunits
Inactive: R's bound to C's
Active: R's release C's to PHOSPHRYLATE PROTEIN SUBSTRATES ON SER/THR side chains. |
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Term
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Definition
| GlycogenPhosprylase Kinase or CREB transaction factors. |
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Term
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Definition
1)Hydrolysis GTP so GDP binds to alpha
2)Cleavage of cAMP by phosphodiesterases |
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Term
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Definition
Smooth Muscle Relaxation by
-phosphyrlates MYOSIN LIGHT CHAIN KINASE and PHOSPHOLAMBAN = increases reuptake of calcium into sarcoplasmic reticulum = reduced calcium levels |
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Term
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Definition
| -produced by membrane bound or cytosolic/soluble enzymes |
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Term
| what is the importance of NO in cGMP? |
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Definition
Soluble forms of cGMP are activated by NO, which are formed by NOsythase.
-Since NO is LABILE, it can difuse and act locally on aterial smooth muscle (i.e. Viagra) |
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Term
| exceptions of cGMP activity? |
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Definition
EYE rods and cones.
-instead of using PKG, uses Na and Ca, where in the dark, high cGMP concentrations are presnt to keep Na/Ca channels open = depolarizing the membrane. |
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Term
| Process of Eye activity when light hits |
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Definition
| Light absorbed into GPCR (rhodopsin) -> activate G-protin G-t-alpha -> cGMP Phosphodiesterase (PDE) -> decrease cGMP -> close Na/Ca -> hyperpolarization. |
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Term
| other second messengers of GPCR: IP3 and DAG |
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Definition
Created by PLC-Beta, which itself is from Gq and Go.
IP3 then activates on Ca by telling SR to release so influx of cytosol CA. |
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Term
| What does Ca do as a GPCR second messenger |
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Definition
| Calmodulin binds 4 Ca molecules via its EF HAND, then activates enzymes or PKC |
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Term
| NOTE: there is cross talk between different signal transduction... |
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Definition
| such as between cAMP with IP3/DAG. |
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Term
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Definition
Stepwise dephos, see, IP3 go to 2 than IMP, then Inositol.
*The last dephospho is UNOSITOL-1-PHOSPHATASE, which can be inhibited by LITHIUM. |
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Term
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Definition
DAG is phosphyrlated by PHOSPHATIDIC ACID.
*Note, termination is phosphrylated, not dephosphyrlated like with IP3. |
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Term
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Definition
1) Reuptake by ER via Ca ATPase pump
2) Ca kicked out of cell from intraceullular fluid
3) Na/Ca exchanger. |
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Term
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Definition
| aka RECEPTOR DESENSITIZATION -tachyphylaxis, refractory, adaptation, down-regulation... |
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Term
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Definition
2 Mechnisms
1) Receptor phosphorylation
2) Receptor internlization aka SEQUESTRATION |
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Term
| What is Receptor Phosphorylation |
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Definition
PART 1 of RECEPTOR DESENSITIZATION:
Ser and Thr is phosphylated by Kinases which decreases its binding affinity to G-proteins.
*PKA can phosphyrlate it, but also other GPCR's = HETERLOGUS DESENSITIZATION |
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Term
| What is RECEPTOR INTERNALIZATION |
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Definition
Part 2 of Receptor desensitization.
This is also known as SEQUESTRATION
Uses a scaffolding protein, ARRESTIN, to recruit other proteins in order to intiate a different signal transduction pathway. |
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Term
| Protein phosphylation is done by? Dephosphorylation? |
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Definition
| ATP kinases, which makes it INACTIVE, Protein phosphatases, which makes it Active. |
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Term
| How does phosphorylation make something active/inactive. |
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Definition
It has a highly NEGATIVE CHARGE (-2), which changes the LOCAL CHARGE/HYDROPHOBICITY which causes CONFORMATION CHANGE (primary, secondary, etc) and THUS FUNCTIONAL ACTIVITY.
*in addition, it is a covalent atttachement to free side chain of OH on Ser Thr or Tyr |
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Term
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Definition
| Soluble or membrane bound hormones that attach to ligands to create effects |
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Term
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Definition
1) LIGAND binds,
2) Phosphorylation of tyrosine residues.
3) Adapator proteins like GRB2 and Ras proteins can bind and start reaction |
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Term
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Definition
a GTPase switch protein, is a proto-onconogene - basically when a mutation of Ras = cancer.
It stimulates Raf -> MEK -> MAPk (map-kinase) -> several transcription factors |
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Term
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Definition
TRASTUZUMAB: aka HERCEPTIN
- bind to HER2, receptor, a RTK like EGFR, forming a heterodimer and inhibits it, inducing tumor reduction/regression. |
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Term
| Drugs utiliized as Tryosin kinase INhibitors |
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Definition
CP GE and EV IT
1)monoclonal anitbodies to EGF
CETUXIMAB = ERBITUX
PANITUMUMAB = VECTIBIX
2)Binds to EGFR
GEFITINIB = IRESSA
ERLONTINIB = TARCEVA. |
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Term
| Extrinsic Tyrosine Receptors aka |
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Definition
| Cytokine Receptors. THe kinase function is not a part of the receptor protein, and uses Ligand binding. |
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Term
| Cytokine Receptor Process. |
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Definition
| JAK kinase = no transmembrane region, no ligand binding domain = non-receptor tyorsine kinase. |
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Term
| Cytokine receptrs uses SH2 and PTB domains as |
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Definition
| attaches to phosphotyrosine residues that served as their "docking sites". |
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Term
| INsulin is an example of what type of receptor? |
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Definition
| RTK example where glucose uptake increases, increased glycogen synthesis, glucose for energy, inhibits gluconeogensis, lipid/protein synthesis. |
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Term
| INsulin Signaling cascade of IRS-1 |
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Definition
| activates ras/map kinase to promote activity of insulin/growth! |
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Term
| INsulin signaling by IRS-2 |
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Definition
uses PI-3. (not IP3 of GPCR)to
1) activate PKB = phosphyrlate GSK3 = inhibit it, so glycogen systhesis is stimulated.
*GSK3 = glycogen sythase kinase-3, which means inactivates glycogen sythase...
2)recruit PK to increase upregulation f glucose transport via GLUT4 = increase number of glucose transporters . |
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Term
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Definition
| bind to Tyr-phosphyrlated receptor, dissociate from receptor, dimierize, and the move to nucleus. |
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Term
| Cytokine Signaling Example with EPO. What is it? |
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Definition
| Released from kidneys when low oxygen. It stimulates blood cell production by preventing apotpsosis. |
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Term
| Cytokine Signaling: EPO, MOA |
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Definition
| Binds to receptor => phosphyrlation => JAK-2-Stat5 activation = >transcriptional activation |
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Term
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Definition
A) STAT5
B) GRB2/SHC -> RAS -> MAPkINASE
C) PLC -> increase Ca
D) PI-3 -> PK-b |
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Term
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Definition
1)PhosphoTyrosine Phosphatase = inactivate JAK's
2) Feedback Loop = STATS
3) Desensitization *think same thing as GPCR's. SO basically...receptor phosphorylation and internilization. = phosphylation and recruiting other cytosolic proteins (via Arrrestin) |
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Term
| Protein Cleavage achieved by? |
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Definition
| Proteolytic degradation of a protein (think NF-KB signalling)when TNF or IL-1 activates.... |
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Term
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Definition
| It is present in the cytosol as inactive, but when "stress" will be "rapidly activated" |
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Term
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Definition
| TNF and IL-1 -> phosphrylates I-KB Kinase (does poly0ubiquetinaiojdion) -> free NFKB goes to nucleus = gene transcription. |
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Term
| Difference between RTK and Cytokine Receptors |
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Definition
| Cytokine receptors are transmembrane receptors with no kinase activity of their own, but RTK's DO!... |
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Term
| Characteristics of Ion Channels |
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Definition
1)Fast!
2) Combines receptor and effecto function
ex. Nicotinic AcH receptor |
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Term
| Nicotinic is an example of? What does it do? |
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Definition
Ligand Gate Ion Channel.
It control pore for Na and Ca and uses AcH as its endogenous ligand. |
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Term
| 3 types of Nicontic Receptors |
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Definition
Depolarization in
1) Muscle:
2) Neronal (CNS)
*distinction between the two: Only muscle Nic Receptor binds the snake venom toxins with high affinity. |
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Term
| Drugs utilizing Nictonic (Ion Channel Receptors) |
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Definition
Curare, to achieve muscle relaxation by blocking nicotinic receptors
and VARENICLINE = an agonist for CNS for smoking cessation. |
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Term
| Structure of Nicotonic Receptor |
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Definition
Pentameric Structure with 4 membrane domains.
Uses ASP and GLU side chains via M2 Transmembrane segment on the hydrophobic alpha helix.
PORE |
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Term
| Basal State of Nictonic Receptor |
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Definition
| AC is abound on alpha subunit, where two ligand molecules have "cooperative behavior, so that the whole pentamer changes. Otherwise channels are closed at the basal state. |
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Term
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Definition
1) LIgand Gated = Gaba and Nicotonic
2) Voltage Gated. |
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Term
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Definition
Anion channel for Cl-
Also pentameric, just like nocotinic.
with 6 alpha, three beta, three gamma, and one delta. |
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Term
| So what's the difference between gaba and nictonic? and what does it do differently? |
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Definition
Its a Inhibitory thingy.
It opens chnannels for Cl- so it's actually hyperpolarizing, no depolozrizing. |
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Term
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Definition
Benzodiaspaine: has allosteric sites for ...
1) BZ agnists bind to enhance GABA
2) BZ antagonist blocks agnoists, otherwise no activity.
3) Inverse negativel alloster modulators to inhibit Gaba |
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Term
| Any other drug/chemical regulators of GABA? |
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Definition
1) Ethanaol, Barbiturates, and Steroids.
2) Znion specifically block GABA receptors and its known that convulsants block GABA too in order to enhance excitability. |
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Term
| To review, what the ion channels, and are there others? |
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Definition
The main ones are Ligand Gate Ion Channels, and GABA.
Other examples include:
1) Ionotropic Glutatamate/Aspartate Receptors (AMPKA; KAINATE; NMDA)
2) Serotonin 5HT
*the first two are excitatory
3) Glycine Receptors = iNHIBITOR. |
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Term
| Difference between voltage gated K, Na, and Ca |
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Definition
Tetramers = K
Na and Ca = large monomers |
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Term
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Definition
1)4th transmembrane = voltage sensor
2) PLoop formed from segments 5 and 6
3) Loops form CLOG for the PORE = inactivate channel.
4) has alpha = activating
5) beta = regulatory. |
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Term
| Drugs and Voltage Gated Ion Channels |
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Definition
1) Anesthetics
2) Antiarrhythmics
3) Antieplipetics
4) Antihypertensives |
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Term
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Definition
| act on Na Channels to block action potentials |
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Term
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Definition
| can act on ligand and voltage ion channels |
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Term
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Definition
| Na channel blockers (again, like anesthetics) |
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Term
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Definition
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Term
| of the voltage gated channels, which one is most heterogenous? |
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Definition
POTASIIUM CHANELS!
so lots of drug targets. |
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Term
| name some examples of NUCLEAR RECEPTORS as a drug target |
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Definition
CAD SLT (CAD Stream-Load Time)
1) Corticosteroids
2) Vit A
3) Vit D
4) Steroids
5) Lipids
6) Thyroid |
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Term
| Nuclear receptors all belong to? |
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Definition
| Transcription Factors family where they bind to DNA targets called REGULATORY elements. |
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Term
| Characteristics of Nuclear Receptors |
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Definition
All are Transcription Factors
Contain 3 distinct domains |
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Term
| How do Nuclear Receptors Act like TF? |
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Definition
Have Zince Finger ptortines.
Exisit as homo or heterodimers
Have various DNA domains , binding, activation, flexible |
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Term
| the 3 distinct domains of Nuclear Receptors |
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Definition
1) Activating (NH2 Terminal)
2) Dna Binding = Zinc Finger
3) Ligand Binding (COOH terminal) is conserved and not vary. |
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Term
| Nuclear Receptors: Characteristics of HomoDimers |
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Definition
1) exist in cytosol if no ligand
2) Inverted Repeats
3) tyype 1 receptor |
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Term
| Characteristics of Nuclear Heterodimers |
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Definition
RXR is partner
Direct repeats at varaible distances
remain in nucleaus even if ligand is present
Type 2 receptors. |
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Term
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Definition
Homo:
1) If no ligand, exist in cytosol,
2) Type 1
3) Inverted Repeats
Hetero
1) Type 2
2) Direct repeats at variable distances
remain in nucleaus with or without ligand
aka RXR |
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Term
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Definition
| Short consesus DNA seqeuences with inverted repeats or direct repeats. |
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Term
| Endogenous ligands that bind to GPCR |
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Definition
Muscarni,
adrenergic
angiotensin,
dopamine,
histamine
opoid
Serotonin (hydoxytryptamine) |
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