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60 Cards in this Set
- Front
- Back
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What is zero-order kinetics?
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-rate of change in concentration that occurs at a fixed amount per unit time
-such as saturation of mediated or active transport processes -equation: Ct=Co-Ce (vmax) |
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What is first-order kinetics?
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-rate of change in concentration in proportional to concentration of chemical available for the reaction or process
-includes diffusion, subsaturation of mediated or active transport processes -equation: Ct= Cox ek |
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What occurs during one-compartment open model?
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-measured with A(mass)=Co x Vd= excrection, elimination, and metabolism
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What is involved in first-order absorption and elimination?
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-absorption efficiency (F) (<1.0) X fraction of administered dose (D) absorbed
-absorption rate |
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What occurs during saturation of drug-protein concentrations during absorption? consequnces?
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-active uptake: reduced plasma levels and AUC after oral but not IV doses
-first-pass metabolism: increased plasma levels and AUC after oral but not IV doses |
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What occurs during saturation of drug-protein concentrations during distribution? consequences at high dose?
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-plasma protein: increased Vd, increased glomerular filtration, increased hepatic clearance (if extraction ratio is low)
-tissue protein: decreased Vd, graph of Ct/Cp against Cp will be linear |
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What occurs during saturation of drug-protein concentrations during metabolism? consequences during high dose?
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-metabolism enzymes (saturation by substrate, depletion of cofactors, product inhibition): decreased clearance, AUC/dose ratio increased for parent compound, AUC of metabolite/dose ratio may decrease by both oral and IV, enzymes with high Km values may handle large proportion of the dose
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What occurs during saturation of drug-protein concentrations during excretion? consequences during high dose?
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-renal tubular secretion: decreased renal clearance, AUC/dose ratio increases for oral and IV, non-renal routes used for elimination, total excretion in urine per dose may decrease
-renal tubular reabsorption: opposite effects for saturation of renal tubular secretion -biliary excretion: decreased biliary clearance, decreased enterhepatic recirculation, renal route may become more important for excretion, AUC/dose ratio increases for oral and IV doses |
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What is the nephron function?
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-excretion of drugs
-lipid soluble and nonionized drugs are passively reabsorbed throughout the tubule -distal segments have secretion of hydrogen favors reabsorption of weak acids and weak bases -active secretion of roagnic acids and bases occurs only in the proximal segment -input=output |
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What is filtration?
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-occurs in the glomerus
-input=output -Clreneal/GFR = 1 -bulk flow process |
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What is reabsorption?
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-occurs in tubules
-lipid soluble drugs get reabsorbed b/c lipid soluble are the ones gthat get absorbed in thee first place -input<output -Clrenal/GFR < 1 |
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What i secretion?
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-input<output
-Clrenal/GFR > 1 -occurs in tubules |
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What are organic anion transporting polypeptides (Oatp1) as renal transporters?Substrates?
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-sodium-independent organic anion transport
-substrates include pravastatin and enalapril |
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What are organic anion transporters (Oat1 and Oat3) as renal transporters? substrates?
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-dicarboxylate exchanger
-substrates include para-aminohippurate, methotrexate, B-lactam antibiotics, NSAIDs, and antiviral nucleoside analogs |
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What are multidrug resistance associated proteins (Mrp2)as renal transporters?
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-can cause dubin-johnson syndrome and eisai hyoerbilirubinemic rat
-substate include glutathiuone conjugates, glucuronide, and on-conjugates organic anions (pravastatin, methotrexate, and irinotecan) |
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What are the substrates for sodium phosphate cotransporter (NPT1)?
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-substares include benzylpenicillin, mevalonic acid and foscarnet
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What is renal clearance?
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-rate at which a substance (x) is removed from blood or plasma by renal mechanisms
-Cl(renal)=UxV/P -Cl(renal)= glomerular filtration rate and renal blood flow -ke= rate constant of elimination -dc/dt=keC -ke=Clearance/Vd T1/2 (elimination)=.693(Vd/Cl) |
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What is the relationship between clearance, rate constant of elimination, and elimination half-life for a drug eliminated by the renal route?
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-drugs distributed in plasma water has the greatest concentration and the shortest half-life
-drugs in extracellular fluid and body water had a lower concentration but a longer half-life of elimination |
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How do you assess the nature eof renal drug transport to measure clearance of drug relative to inulin or creatine (GFR marker)?
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-priming dose of drug and inulin (or creatinine)
-maintain constant plasma concentration by continuous infusion for remainder of experiment -once stabilized, several clearance determinations are performed: [X]urine, rate of elimination, and [X]plasma -ratio of clerances of X/inulin or creatinine are determined |
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How do you interpret the ratio between drug assessed during renal clearance and inulin/ creatinine?
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- > 1: drug excreted in part by activee secretory mechanism
- < 1: drug filtered and (partially) reabsorbed - = 1: drug filtered but not appreciably reabsorbed or secreted |
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How do you assess the nature of renal drug transport and urinary pH?
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-vary the urinary pH and look for effect on clearance relative to inulin
-if drug is an acid or base and is passivly reabsorbed, urinary pH changes may change the ratio of drug clearance/inulin clearance |
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What occurs during urinary acidification?
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-enhanced excretion of bases
-enhanced reabsorption of acids |
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What occurs during urinary alkalinization?
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-enhanced excretion of acids
-enhanced reabsorption of bases |
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What are varioussn active transport inhibitors?
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-probenecid
-PAH -tetraethylammonium (TEA) -N-methylnicotinamide |
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What is the law of mass action? assumptions?
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-L+R<--> LR
-rate of association: k1 -rate of dissociation: K-1 -k-1/k1=Kd -binding iss totally reversible -reactants exist only as free or bound species -all receptor sites have equivalent affinity for ligand and are independent -such as phenoxybenzamine: covalent bonds with alpha receptors |
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What is the equation for the scratchard plot? significances?
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-B/F= [Bm]/Kd-[B]/Kd
-m= -1/Kd X= [B] Y= B/F -steeper the slope, lower Kd -lower max concentration of bound ligand, receptors are more quickly occupied -if you have different Bmax's, then you must hvae different receptors -if same Bmax, top line has greater affinity |
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What experiments can you use to determine the affinity of specific lignads to receptors?
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-By either enzyme-immuno assay
- or radiolabeling |
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What are considrations in developing a radioligand binding assay?
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-receptor concentration 10^-12 to 10^-8M (fmol to pmol per mg wet tissue weight
-high affinity: ligand-receptor dissociation constant is in the range of receptor concentration -high selectivity: ligand binds to only one type of receptor with minimal binding to nonreceptor components, proteins are sticky -high specific radioactivity: so that extremely low concentrations may b easily and accuratly determined |
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What are radioligands in radioligand binding assays?
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-purified
-has specific acitivity -high affinity (slow dissociation) -chemically stable under conditions of assay |
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How do you prepare tissues for radioligand binding assays?
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-try to get receptors as pure as possible
-whole tissues have low receptor density -homogenates have partial purification and concentration of receptor "material" (you get alot of non-specific binding) |
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What is the procedure of filtration for radiolabel binding assay?
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-Have 2 groups: 1 with justs radioactive ligand and 1 with an unlabeled competitor
-homogwenize and centrifuge plasma membrane fraction of target tissue with receptor -incubate at 37 deg. C for a given time -then filter each sample undere vacuum through glass filters (bound attaches to filter) -rinse with 5-10 mL of ice-cold buffer or saline solution -liquid is then uncovered and then assayed for radioactivity (="free" labeled ligand in scratchard analysis) -filtered assayed for radioactivity (dpm)(total binding) -From both groups you get total bound and non-specific binding -subtract both groups to get specific bound labeled ligand |
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What are the disadvanatages of scratchard analysis?
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-distortion of experimental error
-violates assumptions of linear regression because specific binding is written twice, no dep. vs. indep. |
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What are competitive binding experiments? applications?
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-binding of single concentration of labeled ligand in the presence of various concentrations of unlabeled ligand
-has assay validation -has chemical entity screening (high-thoughput) -low affinity ligands |
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What is the occupation theory based on drug-response relationships? Equations?
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-bindign is reversible
-magnitude of drug effect (response) is proportional to fraction of receptors occupied -one drug molecule combines with one receptor -maximal effec when all receptors occupied -Kd=[D][R]/[DR] -Kd=[D](Rt-[DR])/[DR] -[DR]/[Rt]=[D]/Kd+[D] -Rt=total receptor concentration= [R]+[DR] |
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What is efficacy in drug-response relationships? Equations?
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-ability of a ligand to produce a maximum response
-E=Emax[D]/Kd+[D] |
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What is Kd in drug-resposne relationships? EC50?
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-concentration of drug that occupies 50% of receptor sites
-concentration of drug that produces 50% of maximal response-when there is a linear relationship, then EC50=KD |
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What is intrinsic activity of drug-response relationships? Equation?
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-proportionality constant (A)
-maximum effect produced when drug occupies receptor -E=a[DR] |
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What is the concept of efficacy for drug-response relationships? Equations?
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-non-linear relationships between receptor occupancy and drug response
-agonists produce equal responses while occupying different proportions of receptors -response (R) of tissue is a function of stimulus (S) -drugs have 2 independent properties: efficacy adn affinity -R=f(s) -S=ey -where e= efficacy and y= fractional response |
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What is efficacy (power) of drugs based on the concept of efficacy and drug-response relationships?
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-describes the biologic effectivness of the drug-receptor complex
-related to Bmax or Emax -not used to define a receptor -full agonist produces maximal efficacy (e=1.0) -partial agonist produces less than maximal efficacy (e 1.0) -antagonist produces no effect (e= 0) |
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What is affinity (potency) of a drug based on the concept of efficacy of drug-response relationships?
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-KD
-describes the tendency of a drug to form a stable drug-receptor complex -used to define receptors |
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Whata re drug antagonists as a concept of drug-response relationships? What is the schild ration?
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-bind to receptor with efficacy=0
-competitive (reversible) antagonists= inhibition surmountable -shift in apparent KD (lower affinity) -unaltered Emax -realtionship between EC50 (antagonist) and EC50 (agonist) |
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What is the criteria to define a competitive antagonist?
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-blockade selective for family of agonists acting on single receptor type
-blockade in different tissues by series of antagonists should show identical rank order of potency -reversible blockade -for single competitive antagonists, KI should be identical for differenmt agonists acting at same receptor -values for KI derived from studies assessing tissue response should be identical to KI derived from bindign studies |
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What is non-competitive (irreversible) antagonist of drug-response relationships?
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-does not allow agonist to produce a maximal effect
-shift in Emax (reduced efficacy) -unaltered KD |
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What is the onset of statin-HMGCoA reducatase enzyme receptor? half-life? amplification? specificity/ selectivity?
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-rapid onset
-half-life defined by threshold and concentration of transmitters in plasma -no amplification (IC50=KD) (max effect= max binding) -specificity/selectivity is high |
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What is a receptor?
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-an cellular molecule to which drug binds to initiate effect
-includes ligand-binding domain -effector-domain -cellular target (effector proteins, transducers, and second messengers) |
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What is the mode of action of plasma membreane receptors by cation channels? anion channels? adenylate cyclase? phospholipase C? tyrosine kinase? other candidates?
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-Na+, K+, and Ca2+
-Cl- -stimulation, inhibition -stimulation, inhibition -stimulation -gyuanylate cyclase stimulation, phospholipase stimulation, and Na+/H+ exchange stimulation |
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What is the mode of action of intracellular membreane receptors for transcriptional regulation? Translational regulation?
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-direct binding to promoted or enhanced regions of the gene in the 5' regions or selected introns or by associated and regulation of other DNA binding that bind to these receptors
-affects RNA secondary structure and its stability of translation efficency |
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What is the onset of activity of epidermal growht factor receptors? half-life? accumulation? specificity/selectivity?
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-fast onset
-long duration -no accumulation: EC50= KD -high selectivity |
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What is the pathway of activation of epidermal growth factor receptors as ligand-regulated transmembrane enzymes?
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-after binding of EGF to receptor, converts from nactive monomeric state tio an active dimeric state, where polypeptide receptors bind non-covalently
-cytoplasmic domains become phosphorylated on tyrosine residues and enzymatic activities are activated -catalysing phosphorylation of substrate proteins |
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What is the onset of activity of cytokine receptors? half-life? amplification? selectivity?
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-rapid onset
-short half-life -large amplification (EC50<KD) -selectivity depends on combination of receptor subunits |
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What si the pathway of activiation of cytokine receptors as ligand-regulated transmembrane enzymes?
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-after activation by ligand and becomes dimerized,mobile protein tyrosine kinase molecules (JAK) are activated
-phosphorylation of signal transducers and activation of transcription (STAT) molecules occurs -STAT dimers travel to nucleus tio regulate trasncription |
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What is the onset of activity of acetylcholine receptors? half-life? accumulation? specificity/selectivity?
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-fast
-large amplification -short half-life -has selectivity for multiple substrates |
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What is the onset of activity of GABA receptors? half-life? accumulation? specificity/selectivity?
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-delayed (prolonged) onset
-short half-life -amplification occurs (EC50<KD) -selective for multiple substrates |
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What is the onset of activity of G- protein receptors? half-life? accumulation? specificity/selectivity?
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- rapid onset
-duration increases with binding -amplication exists (EC50<KD) -has selectivity to multiple substrates |
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What is the pathway of activation of G-proteins?
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-agonist produces receptor active state that goes on to interact with the G-protein
-confromational change in g-protein causes bound GDP to exchange with GTP -triggers dissociation of G-protein complex into alpha and Beta-gamma subunits -these interact with effectors such as senylate cyclase and calcium channels -alpha subuit hydrolyses bound GTP back to GDP an inactivated alpha psubuint reasscoiates with beta-gamma subunits to repeat cycle |
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What are the activators and cellular effects of Gs type proteins?
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-B-adrenergic amines, glucagon, histamine, and sertonin
-stimualted adenylate cyclase and activated calcium channels |
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What are the activators and cellular effects of Gi type proteins?
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-alpha 2- adrenergic amines, acetylcholine (muscarinic), opiods, serotonin
-inhibits adenylate cyclase -activates potassium channels |
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What are the activators and cellular effects of Gq type proteins?
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-muscarinic, bombesin, and serotonin
-activates phospholipase C |
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What are the activators and cellular effects of Go type proteins?
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-neurotransmitters in brain
-inhibits calcium current |
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What are the activators and cellular effects of Gt type proteins?
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-photons (rhodopsin and color opsins in retinal rod and cone cells)
-stimulates adenylate cyclase in the eye |
