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Pharmacology > membrane bound receptors > Flashcards

membrane bound receptors Flashcards

1
Q

Receptor

A

protein or group of proteins usually embedded in the cell membrane that allows cell to collect information about its surroundings

*sensing element in the system
coordinates the function and responses of all the different cells in the body

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2
Q

Ligand

A

chemical messenger that induces conformational change in receptor

*neurotransmitter, molecule, peptide, hormone-endogenous molecule

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3
Q

Conformational change

A

changes the shape of receptor that induces a downstream transduction

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4
Q

Properties of receptors

A
  • normal points of control of physiologic processes
  • function is regulated by molecules supplies by body
  • drugs can only mimic or block body’s own regulatory molecules (will not give a cell new function)
  • fluctuate between different natural configurations (some configurations are associated with being active, partially active and inactive)
  • drugs can activate/ inactivate receptors by stabilizing conformation
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5
Q

Drug- receptor activity

A

drugs interact with receptors and produce varying effects

therapeutic response

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6
Q

Affinity

A

how well a drug binds to a receptor

synonymous with potency

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7
Q

Potency

A

AFFINITY
[[more potent lower drug]]

*can differentiate between agonists that activate the same receptor

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8
Q

Efficacy

A

INTRINSIC ACTIVITY

  • ability to produce desired response expected by stim of given receptor
  • max possible effect
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9
Q

Agonist

A
  • binds to receptor and triggers a response
  • mimics endogenous ligand
  • stabilizes the active form
    ex. Propofol and GABA

3 type

  • full
  • partial
  • inverse
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10
Q

Full agonist

A

max activation of all receptors

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11
Q

Partial agonist

A
  • activates receptors but not max response
  • weakly stabilizes active state, or stabilizes a partial active state
  • decreased efficacy (desired effect) then full agonist
  • blocks full response
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12
Q

Inverse agonist

A
  • binds and causes opposite action of agonist
  • stabilize the inactive state
  • prevents any endogenous activity at receptor
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13
Q

Antagonist

A
  • affinity for receptor (binds to receptor) but no efficacy (no desired effect)
  • no activation, block endogenous chemical response
  • fluctuation in confirmation continues as if nothing was there
    ex. ketamine and labetalol on inotropic glutamic NMDAR

2 types

  • competitive
  • noncompetitive
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14
Q

Competitive antagonist

A

-reversible; weaker bonds
(ionic, hydrogen, Vander waals)

-can be over come with higher concentration of drug

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15
Q

Noncompetitive antagonist

A
  • irreversible; strong covalent bond
  • can not be displaced
  • higher concentration of drug can not overcome
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16
Q

Tolerance

A

increased drug concentration required to produce a given response

-caused by up/ down regulation of enzyme induction

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17
Q

Tachyphylaxis

A

-very rapid development of tolerance

18
Q

Orthosteric

A
  • binds to same site

* can be agonist or antagonist

19
Q

Allosteric

A

-binds to an alternative/ accessory site

prevents the conformational change

*can be agonist or antagonist

20
Q

Porer blocker

A

antagonist

physically obstructs/ blocks channel

ex. NMDAR blocked by Mg

21
Q

Overview of Ligand gated ion channel

A

location : membrane
effector : ion channel
coupling : direct
structure : subunits surrounding central pore

ex. Nicotinic AChR (excitatory)
GABAa receptor (inhibitory)
22
Q

Overview of G-Protein Coupled Receptor (GPCR)

A

location : membrane
effector : channel or enzyme
coupling : G protein or arresting
structure: subunits comprised of 7 transmembrane helices with intracellular G-protein coupling domain

ex. Muscarinic AChR
Adrenergic receptors
^both class A

23
Q

Action Potentials

A

neurons, muscle cells and cardiac cells produce APs to communicate with each other

Voltage gated ion channels propagate AP

24
Q

Ligand Gates Ion Channels

A

aka inotropic receptors
-fast transmission
-composed of subunits arranged around a central ion pore
-pentamer (5 subunits)
-tetramer (4 subunits)
both arranged in a circular way to allow ions through

major families;

  • cys-loop receptos (pentamer 5 subunits)
  • ionotropic glutamate receptors (tetramer 4 subunits)
25
Q

Cys-Loop receptors

A

Ligand gated ion channel
pentamer (5 subunits)

-named for the loop formed by disulfide bond between 2 cysteines near the N-terminus

  • Five types of subunits: α, β, γ, δ, ε
  • up to 5 but doesn’t have to be all five

ex. NAChR in muscle –> 2α, β, γ, δ,
NAChR in CNS –> only α, β

excitatory; nAChR, serotonin receptors, 5HT

inhibitory; Glycine, GABAa

26
Q

Gating

A

How Cys-Loop works;

second transmembrane domain of α subunit usually obstructs the ion pore

agonist binds to α subunit and changes the conformation, moving the obstruction and allowing flow through pore

27
Q

Drugs that act on Ligand gates channels

A

Cys- loop receptors;
nAChR;
- Nicotine
-Varenicline (Chantix) ;partial agonist –> help quit smoking

GABAa receptors;

  • Ambiem
  • Alcohol
  • Barbiturates (phenobarbitals; dilantin, thiopental)
  • Benzodiazepines (diazepam; valium, lorazepam; valium)

Inotropic Glutamate Receptors
NMDA receptors;
-Ketamine; noncompetitive antagonist (effect; sedation, amnesia)

AMPA receptors;
-Aniracetam; cognition/ memory enhancer by stimulating AMPAR

28
Q

Nicotinic Acetylcholine Receptors (nAChR)

A

excitatory cys-loop ligand gated ion channel

  • located at NMJ and CNS;
  • NMJ nAChR contain a, β, δ, and γ subunits
  • Neuronal nAChRs contain only a and β subunits

Receptor state;

  • closed
  • open
  • desensitized

excitatory; pass Na+, K+ and Ca++
Cys- loop; Pentamer;5 subunits

in the brain nAChR up regulates in response to chronic nicotine
smokers have 2x more nAChR receptors than nonsmokers
*this is why its hard to quite ;

29
Q

nAChR desensitized state

A
  • not open or closed
  • higher the affinity ligand for the receptor the more likely to desensitize
  • only thing that can relieve it is time
30
Q

Ionotropic Glutamate Receptors

A

ligand gated ion channel

  • composed of 4 subunits (tetramer)
  • each subunit has 4 transmembrane domains
  • second transmembrane domain forms ion pore
  • each subunit has its own binding site
  • not all binding sites are for glutamate

Types;

  • NMDA receptors
  • AMPA receptors
  • Kainate receptors
  • only excitatory; pass Na+, K+ and NMDAR pass Ca++
31
Q

NMDA receptors

A

Ligand gated ion channel
inotropic glutamte receptor

  • 2 binding sites for glutamate
  • 2 binding istes for glycine
  • all 4 binding sites with 2 of each enzyme must be filled for channel to open
  • at resting membrane potential NMDAR blocked by Mg
  • NMDARs “coincidence detectors”
32
Q

Long term potentiation

A

Both NMDA receptors and AMPA receptors are located in the post synaptic terminal of a synapse

-AMPA receptors are activated first/ faster and can be activated by a weak stimulations and can create a slight depolarization of a cell, at that same time when glutamate binds to NMDAR only a few ions flow through channel bc it is blocked by Mg++

  • with frequent AP AMPAR can generate a larger enough depolarization will cause Mg++ to leave bc the cell will be more postive
  • depolarization relieves the block and allows NMDAR to open
  • NMDAR open and passes Ca++, which binds to calmodulin and activates CaMKinase (CaMKII) which leads to an upregulation of AMPARs on the synapse
  • more AMPARs = stronger synapse

**NMDARs are coincidence detectors –> only activate when cell is activated or AP happens in quick succesiolns
^multiple AP needed to move Mg++ block

33
Q

G-Protein Coupled Receptors

A

aka 7 transmembrane receptors

  • slower signaling than ligand gated ion channels (neurotransmitters use both)
  • rely on second messenger for signaling
  • 3% of our genome dedicated for GPCR coding
  • target for more than half of current pharmaceuticals

-α, β, γ, subunits
^most drugs target α

3 main classes

  • class A;
  • adrenergic receptors
  • muscarinic AChR
  • class B;
  • parathyroid hormone (PTH)
  • class C;
  • metabotropic glutamate receptor
  • GABAb receptors
34
Q

Activation of GPCR

A
  • Second messenger system
  • α subunit has GDP sitting on it
  • when agonist binds to receptor the α subunit moves over and attaches to it
  • GDP is kicked out and turned into GTP
  • α subunit ATP dissociates and is free to activate an effector
  • activation is terminated when the GTP molecule is hydrolyzed, which allows the α subunit to recombine with β, γ
  • single agonist-receptor complex can activate several G-protein molecules
35
Q

Gα subunits

A

Gαs; activates adenylyl cyclase and increases cAMP

Gαi; inhibits adenylyl cyclase and decreases cAMP

Gαq; activates phospholipase, phosphoinositol hydrolysis;
increases IP3 (inositol triphosphate) and DAG (diacylglycerol);
which releasesCa++ from intracellular stores and activates protein kinase
36
Q

Direct G-protein

A

βγ subunits of G i & G o proteins, appears to be a general mechanism for controlling K + and Ca 2+ channels.

37
Q

Cholera Toxin

A
  • its internalized by the cell.
  • disrupts the conversion of GTP to GDP
  • increased levels of GTP lead to abnormally high cAMP levels
  • increased cAMP activate Cl ion pump and releases Cl into intestinal lumen
  • NA+, K+ and bicarb ions follow leading to more water being. held in intestinal lumen to balance osmolarity
  • diarrhea
38
Q

GPCR Desensitization

A
  • ligand is bound to G-protein coupling receptor for prolonged period of time
  • recruit another protein β-arrestin binds to the receptor
  • blocks the signal tagging it for cell to internalize
  • contributes to drug tolerance
39
Q

GPCR -β-arrestin complex

A
  • can act as a proton scaffold inside the cell

- can have it own signaling pathway independent of GPCR signaling inside cell

40
Q

CNS depression

A

GABAa [[ligand gated ion channel; cys-loop; inhibitory receptor]]

-increased GABAa affinity –>
prolonged Cl- conductance
[[hyperpolarize]]

*vol anesthetics work on GABA and glycine

Pharmacology (7 decks)

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