EXAM 2 VOCAB Flashcards

1
Q

Pharmacology

A

-science of INTERACTIONS of CHEMICAL compounds with BIOLOGICAL systems
-mechanisms of drug action

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2
Q

Pharmacodynamics

A

-study EFFECTS and ACTION of drugs
-correlation of their EFFECTS with their CHEMICAL STRUCTURE
-looks at drug at site of action: EFFECT and RESPONSE

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3
Q

Pharmacokinetics

A

-study of ADME of xenobiotics

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4
Q

Mechanisms of drug action

A

HOW and WHERE drugs act

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5
Q

Action of drugs

A

Agonist or antagonist

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6
Q

Nature of Drugs

A

-defined by action
-act on receptors
-endogenous drugs (hormones or NT) or xenobiotics
-includes poison/toxins

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7
Q

Drug chemical bond interactions

A

-covalent
-electrostatic
-hydrophobic

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8
Q

Drug shape and design

A

-for receptor specificity
-enantiomers and structural studies

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9
Q

Drug receptor

A

-cornerstone of pharmacology
-INTERACTS with drug and INITIATES chain of events to produce EFFECTS

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10
Q

AGONIST

A

interaction with receptor stimulates response

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11
Q

PharmacoDYNAMIC DR principles

A
  • D + R –> DR for all
    -DR –> effector molecule
    -DR –> coupling molecule –> effector molecule
    -DR –> inhibition of metabolism of ligand –> effector molecule
    -all end in effect
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12
Q

PharmacoDYNAMIC principles

A

-Drug binding first step
-orthosteric or allosteric
-inhibition of metabolism/reuptake
-duration of action can be influenced by receptor and drug

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13
Q

orthosteric site

A

-active site
-binds endogenous substrate
-agonists, antagonists

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14
Q

Endogenous ligand of dopamine receptor

A

dopamine

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15
Q

Allosteric site

A

PAM and NAM

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16
Q

PAM (positive allosteric modulator)

A

-allosteric activator

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17
Q

Purpose of Drug Therapy

A

-produce EFFECT of the drug
-drug must achieve enough CONCENTRATION at it’s SITES of ACTION
-achieve MAXIMUM positive effects while MINIMIZING undesired effects

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18
Q

NO DRUG WILL HAVE ONLY ONE EFFECT

A

TRUE

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19
Q

Drug specificity

A

-AFFINITY for receptor
-DISTRIBUTION of receptor
-MULTIPLE receptors (good and bad)
-ENANTIOMERS
-ACUTE vs CHRONIC effects (tolerance)

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20
Q

Drugs ___ cellular function

A

modify

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21
Q

Sites of drug action

A

in, out, on cell

-may need specifics if i no feel so good

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22
Q

Receptor structure types

A

-regulatory, transport, and structural proteins
-enzymes

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23
Q

Receptors determine:

A

-quantitative relationship between DOSE and EFFECTS
-SELECTIVITY of drug (size, shape, charge, and changes in chemical structure)

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24
Q

Antagonists

A

-bind WITHOUT altering receptor function
-blockers

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25
Q

Data of DR interactions

A

-Receptor BINDING/target engagement ASSAYS
-Functional assays

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26
Q

Receptor BINDING/target engagement ASSAYS

A

-measure static event (receptor-drug binding) not function

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27
Q

Functional assays

A

-assessing signaling events associated with receptor activity
-ion flux, second messenger, etc

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28
Q

Concentration-effect curves

A

-responses to low concentrations of drug increase proportionally
-as dose increases, response increases
-levels off
-linear or semi log (S curve)

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29
Q

linear vs Semi log

A

semi log better

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30
Q

10-90 = 3 log rule

A

3 logs between 10% and 90%
-10% +1 log = 50% (EC50)
-50% + 1 log = 90%

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31
Q

If EC50 = 10, then 90% is

A

100

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32
Q

If EC50 = 10, then 10% is

A

1

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33
Q

10^-7

A

100 nanomolar

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34
Q

9.5 x 10^-7

A

950 nanomolar
-multiply by 100 nM

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35
Q

10^-6

A

micromolar

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36
Q

Affinity

A

-ability of drug to interact with receptor
-KD
-determinant of POTENCY
-one drug can have many for diff receptors
-differ from receptor to receptor

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36
Q

low KD

A

high affinity
tight binding

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37
Q

high KD

A

low affinity
loose binding

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38
Q

Effect of drug is proportional to

A

amount of DR complex formed (receptors bound)

D+R <–> DR –> effect
Ka(on) —>
Kd(off) <—-

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39
Q

rate of association

A

-Ka(on)
-D+R
-binding
-increasing part on dose-response curve

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40
Q

rate of dissociation

A

-Kd(off)
-[DR] splitting
-decreasing part on dose-response curve

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41
Q

KD (dissociation CONSTANT)

A

=koff/kon
=[D][R]/[DR]
-50% of receptors are bound

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42
Q

Drugs can have same affinities

A

but different koff or kon

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43
Q

Fast dissociation

A

low koff

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44
Q

Law of mass action

A

D+R –> DR —> effect

when [D][R] = [DR], KD is concentration where 50% receptors are bound

-50% Bmax=KD

*assumptions made

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45
Q

50% of Bmax

A

=KD

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46
Q

Radio receptor binding assay

A
  1. receptor
  2. add ligand (radio labeled) and let bind
  3. filter out unbound ligand

-count remaining amount of receptors bound to drug

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47
Q

Pharmacological profiling

A

-competition testing several unlabeled compounds simultaneously
-IC50 and Ki

MORE
MORE
MORE

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48
Q

Ki vs KD

A

-KD more generally
-Ki relative

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49
Q

Bmax

A

total # of receptors

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50
Q

Saturation Binding analysis

A

-requires labeled ligand
-not good for HTS
-use of heterologous competition assays for pharmacological profiling

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51
Q

COMPETITION BINDING ASSAY

A

-labeled ligands binding receptors
-look at ability of drug to displace (compete) ligand
-CHeng-Crusoff
-y=%binding, x=[drug]
-IC50
-Ki

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52
Q

IC50

A

-concentration at which 50% binding is inhibited

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53
Q

Cheng-Prusoff equation

A

Ki = IC50/[1+L/KD]

-L concentration of ligand
-KD of ligand

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54
Q

D2 receptors

A

dopamine
-parkinsons
-schizophrenia

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55
Q

H1 receptors

A

-histamine
-allergies
-blockage = sleepy

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56
Q

B1 receptors

A

-heart rate

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57
Q

What parameter is NOT required to calculate Ki from Competitive binding assay data?

Kd of radioligand
Bmax value
IC50 of test compound
Concentration of radio ligand [L]

A

Bmax

all we need : Ki= IC50/[1+L/Kd]

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58
Q

Why cant labs compare IC50 values

A

-dependent on KD of ligand AND ligand CONCENTRATION
-5 kappa deltas vs 500 kappa deltas

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59
Q

selectivity ratio (MOR/DOR) (IC50 drug one/IC50 drug2)

A

lower number is HIGHER affinity for numerator

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60
Q

H1 blockers

A

eepy

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61
Q

Most antipsychotic drugs act as

A

receptor ANTangonists

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62
Q

D1 vs D2 binding measures

A

D2 shows better correlation between AFFINITY/potency and EFFECTIVENESS

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63
Q

if Bmax= 20 KD=

A

10

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64
Q

Antagonist and agonist binding sites are

A

overlapping

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65
Q

Magnitude of drug RESPONSE is influenced by

A

pharmacokinetics and pharmacology

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66
Q

Bmax values

A

-REGULATED by drug treatment as an adaptive response
-receptor running away from abusive ex (antagonist) or running to cool guy (agonist)
=total # of receptors can change

67
Q

Propanolol

A

-B1 blocker
-treat hypertension

68
Q

binding of agonist results in

A

induced fit that activates receptor

69
Q

binding of antagonist results in

A

-induced fit that does NOT activate receptor
-can bind to more of the receptor than agonist
-broader
-blocks coactivators from binding

70
Q

Agonist spectrum

A

-full inverse
-partial inverse
-silent ANTagonist
-partial agonist
-full agonist
-SUPER agonist

71
Q

Potency

A

-DOSE of drug required to produce particular EFFECT
-based on doses that produce similar response
-usually EC50

72
Q

EC50

A

-amount of dose needed to produce 50% response

73
Q

Lower EC50

A

HIGHER potency

74
Q

Efficacy

A

-measure of biological response
-%

75
Q

Strong agonist

A

HIGH affinity
HIGH efficacy

76
Q

maximal efficacy limited by

A

TOXICITY

77
Q

Efficacy v potency graph

A

-% vs log[D]
-functional assay

78
Q

middle log value
ex: between -7 and -6

A

-6.52
=300nm

79
Q

-9, -8.52, -8, -7.52, -7, -6.52, -6 log values

A

1nm, 3nm, 10nm, 30nm, 100 nm, 300nm, 1um

80
Q

Partial Agonist

A

-produces reduced response even at full occupancy
-may inhibit competitively the response to a full agonist
-KD might be same

81
Q

Aripiprazole

A

-partial agonist
-D2 receptor
-schizophrenia and depression

82
Q

Buprenorphine

A

-partial agonist
-opiate receptors
-opioid addiction treatment

83
Q

Buspirone

A

-partial agonist
-serotonin
-Depression

84
Q

Partial agonist effects Opioid example

A

-full agonist hits a %bound to feel euphoria but increasing further [D] = die
-partial agonist goes up to % effect of euphoria and no higher
-Antagonist blocks methadone from binding at all = withdrawal

85
Q

Partial agonist THEORY

A

-normal agonist close loop c of receptor
-partial half close loop c
-antagonist cannot close loop c

-by physical shape of molecule
-partial agonist engages less of the receptor

86
Q

As partial agonist concentration increases

A

-FULL agonist binding decreases
-PARTIAL agonist binding increases
-decreases total response

87
Q

Inverse Agonist

A

-opposite response
-requires constitutive activity
-can be full or partial
-stabilize inactive form of receptor
-response can be altered by other agonists or antagonists
-ex: rimonobant

88
Q

Rimonobant (Acomplia)

A

-Cannaboid receptors
-INVERSE agonist of THC
-reduced hunger but caused depression

89
Q

Constitutive activity

A

-can only work on active conformation of receptor in absence of agonist
-reversed by inverse agonist

90
Q

constitutive activity absent

A

-inverse agonist looks like silent antagonists

91
Q

Constitutive activity present

A

-inverse agonist reverses constitutive activity
-lower response

92
Q

Antagonism types

A

-competitive
-noncompetitive
-irreversible (non competitive)

93
Q

Competitive Antagonism

A

-reversible by increasing dose of AGONIST
-binds active site
-has affinity but not efficacy

94
Q

Agonist dose-response curve in presence of antagonist

A

-shifted right proportional to concentration of agonist
-reduces potency
-C’=C(1+L/KD)
-only KD and EC50 changed
*note multiplication
-Schild plot (functional)

95
Q

Schild plot

A

-can be used to calculate KD of ligand to generate PA2 value
-estimate AFFINITY
-functional

96
Q

Binding Analysis of competitive antagonists

A

affinity generally correlates with potency

97
Q

Magnitude of inhibition (clinical response) depends on:

A

-antagonist concentration
-relative potency between antagonists
-concentration of agonist

98
Q

Noncompetitive Antagonist

A

-allosteric
-cannot be reversed by increasing agonist concentration

99
Q

increase of noncompetitive Antagonist

A

-increase KD
-decrease Emax

100
Q

Irreversible (noncompetitive) antagonist

A

-bind active site
-less easily displaced
-covalent bond
-shifted to the right
-max response still possible bc of SPARE RECEPTORS (resembles competitive)

101
Q

Increase [Irreversible antagonist]

A

-max response decreases as spare receptors are occupied
-this part resembles noncompetitive

102
Q

Irreversible vs noncompetitve

A

need way more information given to figure that out

103
Q

Duration of irreversible antagonist action is dependent on

A

receptor turnover

104
Q

Competitive inhibition graph

A

-brachiosaurus walking (competitive bc it’s a race!)

105
Q

noncompetitive inhibition graph

A

-brachiosaurus eating from a short tree (noncompetitive bc he just having a lil treat!)

106
Q

Spare receptors (receptor reserve)

A

-max response by agonist even when less than 100% receptors bound
-irreversible Antagonists

107
Q

Spare receptors in heart muscle

A

-allows heart to respond to catecholamines at 90% occupancy of irreversible antagonist

108
Q

Spare receptors are dependent of

A

-system/tissues
-effector numbers
-signaling pathway

109
Q

Functional Antagonism

A

-2 drugs influence system in OPPOSITE directions
-each drug unhindered
-histamine offset by epinephrine
-system wide not receptor specific

110
Q

Chemical Antagonism

A

-chemical reaction between agonist and antagonist to form inactive product
-agonist inactivated in proportion to extent of reaction with agonist
-calcium antacids and tetracycline antibiotics
-cyanide and sodium nitrate

111
Q

Allosteric Ligands

A

-not active site
-PAM and NAM
-signalin texture

112
Q

Allosteric actions

A

-antagonism (NAM)
-potentiation (PAM)

113
Q

Allosteric Ligand benefits

A

-increased specificity for receptors with similar orthosteric binding sites
-increased safety due to ceiling effect
-provide more physiological/temporal signaling

114
Q

Temporal signaling

A

-PAM in parkinsons can make more dopamine for movement
-NAM in seizures makes less NT

115
Q

PAM increases

A

Emax

116
Q

Neutral allosteric ligand

A

-displace/block PAM and NAMs

117
Q

PAM safety

A

safer than orthosteric agonists

118
Q

5 types of receptors

A
  1. intracellular
  2. cytokine
  3. tyrosine kinase
  4. ion channel
  5. Gprotein coupled
119
Q

Intracellular receptors

A

-lipid-soluble ligand crosses membrane to work on receptor
-steroids, vitamin D
-work on gene expression

120
Q

Intracelular receptor

A

-DR binds to specific DNA sequences near gene
-stimulate transcription of genes
-target gene regulated
-response

121
Q

Intracellular receptor therapeutic significance

A

-lag period
-effects persist after drug gone bc of slow turnover of proteins
-high affinity
-no correlation between plasma level of hormone and effect

122
Q

Other intracellular receptors

A

-effector enzymes
-adenyylyl cyclase, phospholipase, kinases, phosphatases, ubiquitinases
-any intracellular protein with downstream activity

123
Q

Effector enzymes

A

-regulate cellular function
-intracellular nonreceptor receptor
-translation, transcription, membtane potential

124
Q

Cytokine receptor pathway (JAK-STAT pathway)

A

-cytokine binds extracellular domain
-conformational change
-Janus kinase recruited
-kinase phosphorylates receptor
-recruit STAT protein
-dimerization of stat
-gene regulation by STAT in nucleus

125
Q

cytokine receptor ex

A

IL, IFN, Growth hormone, prolactin

126
Q

cytokine receptors

A

-similar to protein tyrosine kinases
-JAK-STAT
-COVID-19 storm

127
Q

Protein Tyrosine kinases

A

-extracellular hormone binding domain and cytoplasmic enzyme domain with protein tyrosine kinase activity
-inactive kinase
-ligand binds
-dimerization
-phosphorylation
=affinity to bind Grb2
-invoke activation of Ras pathway
=gene transcription

128
Q

tyrosine kinase action

A

-limited by down regulation
-upon ligand binding, endocytosis of receptor is stimulated

129
Q

ion channels

A

-voltage activated
-ligand activated

130
Q

voltage activate ion channels

A

-regulated by membrane potential
-positive ions = more likely to fire
-allosteric site
-local anesthetics

131
Q

voltage-gated ion channels are regulated by

A

-phosphorylation
-G proteins

132
Q

ligand-gated ion channels

A

-mimicked by many drugs
-acetylcholine, GABA, glutamate

133
Q

ligand-gated ion channels mechanism

A

-ligand binds
-signal transmitted across membrane by increasing transmembrane conduction of ion
-alters electrical potential
-FAST –important for synapses

134
Q

steroid receptors

A

-HOURS

135
Q

G protein-coupled receptors (GPCRs)

A

-7 transmembrane receptor
-B receptor
-800 which is alot
-involved in like EVERYTHING
-target of 40% of all drugs
-Gproteins, effectors, 2nd messenger

136
Q

Bonus question

A

1971: Earl Sutherland Jr

137
Q

1971: Earl Sutherland Jr

A

CYCLIC AMP

138
Q

GPCR classes

A

A, B, C
-C is venus flytrap glutamate

139
Q

GPCR 2nd messengers

A

-cyclic AMP and GMP
-Ca2+
-phosphoinositides

140
Q

GPCR signaling components

A

R-G-E

141
Q

GPCR signaling

A

-ligand detected by cell surface receptor (R)
-receptor activates G-protein
-Ga or GBy changes activity of an effector
-effector changes concentration of 2nd messenger = effect

142
Q

G protein cycle

A

-detect ligand
-Ga-GDP inactive
-Ga-GTP or GBy disassociate and activate enzyme
-enzyme releases second messengers

143
Q

G protein subunits

A

-Gas
-Gai
-Gaq/11
-Ga12/13
-GBy

-all regulate adenylyl cyclases and ion channels
-but also lots of others

144
Q

Gas (stimulatory)

A

-INCREASE adenyl cylcases
-Gas and Gaolf

145
Q

Gai (inhibitory)

A

-DECREASE adenylyl cyclases
-Gi1-3, Gao,z,t,g

146
Q

Gaq/11

A

-INCREASE phospholipase C 1B
-Gq

147
Q

Ga12/13

A

Rho guanine exchange factors (recruit)

148
Q

GBY

A

-DECREASE adenylyl cyclases
-open Ca, K ion channels

149
Q

second messengers

A

-cAMP
-Gs-AC-cAMP
-cGMP
-Calcium and phosphoinosotides
-diverse and complex

150
Q

cAMP

A

-stimulates cAMP-dependent protein kinases (PKA)
-specificity depends on substrates of kinases expressed in different cells and through cellular compartmentalization of signaling complexes
-B1 receptor for asthma

151
Q

cAMP effector enzyme

A

-adenylyl cyclase
-converts ATP to cAMP

152
Q

measuring cAMP

A

-nonradioactive approaches
-EPAC (protein based)
-HTRF (fluorecent)

153
Q

Calcium and phosphoinosotides

A

-effector enzyme: Phospholipase C (PLC)
= release of phosphotides and diacylglycerol

154
Q

phosphoinositides

A

-from PLC
=release of calcium

155
Q

diacylglycerol

A

-from PLC
-can activate protein kinase C
-M3 muscarinic receptors in alzheimers

156
Q

cGMP

A

-effector: guanyl cyclase
-cGMP activates kinase (PKG)
-regulated by nitric oxide
-more specific

157
Q

cGMP/NO

A

-breaks down byPDE5

158
Q

viagra

A

-blocks PDE5
-prolongs cGMP/NO

159
Q

more drugs target

A

kinases than phosphatases

160
Q

receptor-induced adaptations

A

-homologous desensitization
-heterologous

161
Q

Homologous desensitization

A

-rapid desensitization
-receptor uncoupling-arrestin binding
-sequestration and fate =
-recycling (dephosphorylation) and
-lysosomal degradation

-ACTIVATED RECEPTOR DESENSITIZES SELF

162
Q

B arrestins

A

-adaptor protein that links GPCRs to MAP kinase pathway

163
Q

Recycling

A

-dephosphorylation

164
Q
A