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Physiology and Pharmacology > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

How did Langley’s experiments give rise to the idea of receptors and cell communication?

A
  • he applied pilocarpine which caused slowing of heart rate and increase in saliva secretion
  • if atropine is applied to heart alone, nothing happens
  • if atropine is applied to heart in presence of pilocarpine, heart rate no longer slows (pilocarpine effect is abolished)
  • atropine antagonises pilocarpine
pilocarpine = muscarinic agonist
atropine = muscarinic antagonist
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2
Q

what resulted from langley’s application of pilocarpine and atropine to salivary glands of dogs?

A
  • application of pilocarpine alone caused increase in saliva production
  • application of atropine alone caused no change
  • application of atropine in presence of pilocarpine caused no increase in saliva production
  • atropine antagonises effect of pilocarpine
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3
Q

What were langley’s experiments with nicotine and curare?

A
  • stimulated a nerve in a chicken leg = contraction
  • applied nicotine to that nerve = contraction
    - therefore nicotine mimics effect of electrical stimulation of nerves
  • applied curare and stimulated nerve = no contraction
    • curare blocks effect of electrical
      stimulation
  • applied curare and nicotine = no contraction - curare antagonises effect of nicotine

therefore nicotine mimics effects of nerve stimulation and curare stops nervous stimulation of muscle

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4
Q

How did langley find out whether nicotine and curare act on the nerve or muscle?

A

he denervated the muscle:

  • applied nicotine to muscle = contraction
  • applied nicotine + curare to muscle = no contraction
  • curare antagonises effect of nicotine
  • both effect skeletal muscle, therefore muscle is the receptive substance
  • nerve would normally release a compound that behaved like nicotine
  • receptors recognise mediators and cause a change in cell function
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5
Q

What were Ehrlich’s experiments and what did they achieve?

A
  • he treated blood with different dyes
  • different cells took up different dyes
  • he proposed interactions occured between dyes and cells with specificity
  • interactions are governed by cell type and the structure/solubility of the dye (AFFINITY)

he found evidence of receptors

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6
Q

What are chemical mediators?

A
  • extracellular signalling molecules
  • e.g. hormones, neurotransmitter, inflammatory mediators
  • they are used in chemical communication
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7
Q

what are receptors?

A
  • receptors are macromolecular proteins which recognise and respond specifically to signal molecules
  • they serve as recognition sites for chemical mediators
  • any protein of a cell that ca bind to a molecule and modulate some activity of the cell
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8
Q

how are chemical mediators detected?

A
  • detected by target cells via receptors on their surface

- receptors bind to specific chemical mediators

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9
Q

what is signal transduction?

A
  • cell signalling that occurs when receptor detects a chemical mediator or an extracellular signal
  • this interaction generates intracellular signals which alter the cells behaviour/function
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10
Q

Can cells express multiple types of receptor?

A

Yes

  • single cells can integrate lots of information
  • most mediators can act on more than one type of cell
  • the same receptor may be expressed by more than one cell type
  • this allows coordinated responses involving multiple tissues/organs
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11
Q

can different receptor types use similar signal transduction mechanisms?

A

Yes

- this allows for amplification of signalling

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12
Q

what are the 4 ways cells can communicate?

A
  1. endocrine
  2. paracrine
  3. neuronal
  4. contact-dependent
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13
Q

what is endocrine signalling?

A
  • communication over long distances
  • chemical mediator is secreted into bloodstream and distributed throughout body and acts on receptors on variety of cells
  • e.g. hormones
  • body-coordinated responses
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14
Q

Give an example of endocrine signalling?

A

Insulin action in the body to control blood glucose levels

type 1 diabetes = loss of insulin secreting cells
type 2 diabetes = loss of response to insulin
drugs used to treat diabetes either mimic insulin or increase signalling through insulin receptor

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15
Q

what is paracrine signalling?

A
  • signal molecules act locally, released from one cell and act on neighbouring cells
  • neighbouring cells can be different cell types or the same cell type (autocrine)
  • mediator doesnt diffuse far, and is stored in vesicles/synthesised on demand
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16
Q

give an example of paracrine signalling

A

inflammatory response of mast cells:

  • mast cells detect allergens and secrete histamine which acts locally
  • histamine causes vasodilation and active neurons to itch
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17
Q

what is the role of nitric oxide as a paracrine mediator?

A
  • generated by endothelial cells

- causes vasodilation and smooth muscle relaxation

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18
Q

what is autocrine signalling?

A
  • paracrine signalling but the mediator acts on neighbouring cells of the same cell type as the mediator-releasing cell
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19
Q

what is neuronal signalling?

A
  • signalling across long distances (metres)
  • more specific and faster than endocrine
  • use synapses to restrict signalling to specific target cells
  • use neurotransmitters as mediators
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20
Q

how can drugs effect neurotransmission?

A

by:

  • altering neurotransmitter synthesis
  • altering storage
  • altering release of neurotransmitter
  • e.g. nicotine, curare, botulinum toxin
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21
Q

what is contact-dependent signalling?

A
  • mediator is anchored on cell surface of the signalling cell
  • direct cell-cell interaction is required for the signalling cell to affect the target cell
  • shortest range of cell communication
  • fastest form of communication
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22
Q

give an example of contact-dependent signalling

A

Delta-Notch signalling in development:

- allows adjacent cells to become more specialised to induce a specific cell fate

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23
Q

how is contact-dependent signalling used in the immune system?

A
  • T cell receptors interact with MHC proteins on APCs to become activated
  • this leads to recruitment of cytotoxic T cells and stimulation of B cells to produce antibody
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24
Q

what are bioassays and how are they used?

A
  • they test the concentration/potency of a substance by measuring the biological response it produces

measurements of:

  • pharmacological activity of new or chemically undefined substances
  • investigating the function of endogenous mediators
  • measure drug toxicity and/or unwanted effects
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25
Q

how did Otto Loewi discover chemical transmission?

A
  • he stimulated the Vagus nerve which innervated the heart, producing some sort of liquid
  • he applied this liquid to another heart, and this heart beat slowed down
    -he stimulated the sympathetic system and caused heart to produce an excitatory fluid
  • when this excitatory fluid was applied to a second heart, it caused heart beat increase
    • he found that this excitatory fluid
      contained adrenaline
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26
Q

What did Loewi discover about atropine?

A
  • when applied to the heart, it inhibited the slowing of the heart by the vagus nerve
  • however, it did not stop the release of the Vagusstoff
  • therefore atropine prevented the effects, not the release, of the transmitter
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27
Q

how did Loewi discover cholinesterase?

A
  • when vagusstoff was incubated with ground up heart muscle, it became inactivated
  • this was due to the enzymatic destruction of acetylcholine by cholinesterase
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28
Q

what did Loewi conclude about physostigmine?

A
  • it enhanced the effect of vagus stimulation on the heart and prevented destruction of vagusstoff by the heart muscle
  • showed that enhancement was due to inhibition of cholinesterase
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29
Q

what did Dale’s experiments conclude?

A
  • acetylcholine was used at NMJ and in autonomic ganglia by using bioassays
  • concluded that neurons could be defined by the neurotransmitter they released
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30
Q

what are the effects of acetylcholine when:

  • released from the vagus nerve
  • released from a motor neuron
A

Vagus nerve:
- cause slowing of heart rate

Motor neuron:
- cause contraction of skeletal muscle

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31
Q

can the same neurotransmitter be used by multiple systems?

A

Yes:

  • they can be used by distinct groups of neurons to control different functions
  • ACh is used in the ANS, CNS, and NMJ with multiple receptor types
  • receptors are what cause the specific effects
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32
Q

How is ACh used in the somatic efferent system?

A
  • ACh is released from motor neurons and bind to nicotinic ionotropic receptors on skeletal muscle
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33
Q

how is ACh used in the ANS?

A
  1. Sympathetic: ACh is released from a preganglionic cholinergic neuron and act on nicotinic receptors on post-ganglionic adrenergic neuron. The adrenergic neuron then releases noradrenalin at blood vessels to cause vasoconstriction
  2. Parasympathetic: ACh is released from preganglionic cholinergic neuron and acts on muscarinic receptors on post-ganglionic cholinergic neruons. The cholinergic neuron then releases ACh to innervate sweat glands, increasing sweating
  3. Sympathetic adrenal medulla: ACh is released from preganglionic cholinergic neurons and bind to nicotinic receptors on adrenal medulla, causing it to release adrenaline
34
Q

what is the experimental criteria that establishes a substance as a mediator?

A
  1. it is released in sufficient amounts to produce an action on target cell in appropriate time frame
  2. application of an authentic sample of the mediator reproduces the original effect
  3. interference with synthesis/release/action modulates the original response
35
Q

how are mediators synthesised?

A
  • synthesis of small molecule mediators is regulated by specific enzymes
  • peptide synthesis is regulated by transcription
  • proteins enter RER where they are packaged into vesicles and are taken to golgi
  • at golgi they are packaged into secretory vesicles and processed
  • they are then released by exocytosis
36
Q

what is constitutive secretion of neurotransmitter?

A
  • occurs continuously and little material is stored in secretory vesicles
37
Q

what is regulated secretion of neurotransmitter?

A
  • occurs in response to increased intracellular Ca2+ and other intracellular signals
  • material is typically stored in significant amounts in secretory vesicles waiting for release
38
Q

what are the two ways mediators can be stored and released?

A
  1. mediator is preformed and stored in vesicles before being exocytosed
    - allows for rapid communication
    - e.g. neurotransmitters, hormones, neuromodulators, cytokines
  2. mediators are produced on demand and released by diffusion/constitutive secretion
    - takes longer
    - e.g. prostaglandins
39
Q

how are neurotransmitters stored?

A
  • early studies in NMJ showed quantal nature of neurotransmission
  • suggested existence of packages (vesicles)
  • cryo-electron microscopy identified these packages as vesicles and SNARE proteins which helped dock them to the cell membrane
  • vesicles involved in exocytosis have synaptotagmin (calcium sensor protein) which is required for membrane fusion
40
Q

how is neurotransmission terminated?

A
  1. cholinergic synapses use acetylcholinesterase

2. other syanpses rely on uptake back into the neuron for reuse

41
Q

what is the step-by-step process of synthesis, storage and release of peptide neurotransmitters?

A
  1. uptake of precursors
  2. synthesis of transmitter
  3. uptake/transport of transmitter into vesicles
  4. degradation of surplus transmitter
  5. depolarisation and AP
  6. influx of Ca2+
  7. release of neurotransmitter by exocytosis
  8. diffuse to postsynaptic membrane
  9. interaction with postsynaptic receptors
  10. inactivation of transmitter
  11. reuptake/degradation of transmitter
  12. interaction with presynaptic receptors
42
Q

what is the definition of a drug?

A

a chemical substance of known structure which produces a biological effect when administered to a living organism

43
Q

what is pharmacology?

A

the study of mechanisms by which drugs affect the function of living systems

44
Q

what are the principles of pharmacology?

A
  1. drug action must be explicable in terms of conventional chemical interactions between drugs and tissues
  2. drug molecules must bind to constituents of cells to produce an effect
  3. drug molecules must exert chemical influence on cells to produce a pharmacological response
45
Q

give an example of a drug which interferes with transporters on target cells

A

Fluxoetine = prozac

- antidepressant which inhibits a transporter for serotonin neurotransmitter

46
Q

give an example of a drug of abuse which target neurotransmission

A

amphetamines:

  • indirectly increase noradrenaline (NA)release by displacing it from its vesicles
  • sympathomimetic action

it does this by:

  1. entering nerve terminal by noradrenaline transporter NET
  2. It enters vesicles via vesicular monoamine transporter VMAT in exchange for NA which accumulates in cytosol
  3. some NA is degraded by monoamine oxidase MAO
  4. some NA escapes in exchange for amphetamine via NET to act on postsynaptic receptors
  5. amphetamine also reduces NA reuptake via the transporter, so enhances action of the released NA
47
Q

what is a sympathomimetic drug?

A
  • drugs which in general mimic responses due to stimulation of sympathetic nerves.
  • directly activate adrenergic receptors or to indirectly activate them by increasing norepinephrine and epinephrine levels
  • chemically these drugs are catecholamines or are structurally similar to catecholamines
48
Q

give an example of a drug that targets ion channels which regulate neurotransmission

A

lignocaine

- blocks Na channels

49
Q

give an example of drugs which target receptors involved in neurotransmission

A

Opium:

  • analgesic and euphoric effects
  • causes constipation and respiratory depression
  • long term use of opiates leads to changes in receptor function, where receptors become ‘tolerant’ of drugs
  • tolerance means higher doses are required of a drug to have a wanted effect
50
Q

how are receptors associated to the cell membrane?

A
  • they are embedded in the membrane, anchored by transmembrane domains
51
Q

how are receptors diverse?

A
  • the outer extended part of the protein recognises different mediators
  • this extended region gives diversity and specificity to receptors
  • there are 25 families of proteins that form receptors
  • there are 100s of subtypes
  • families are determined by shared structural features
52
Q

what is the function of receptors?

A

regulation of cellular processes:

  • chemical recognition and binding: ligand binds on outside the cell and is transduced ti produce a change inside the cell
  • the change inside the cell is an intracellular signal generation: signal transduction
53
Q

what are the 4 main classes of receptors?

A
  1. Ligand-gated ion channels (ionotropic)
  2. G-protein coupled receptors (metabotropic)
  3. kinase-linked receptors
  4. nuclear receptors
54
Q

what are kinase-linked receptors?

A
  • single transmembrane domain
  • amino terminus binding site faces outside the cell
  • involved in immune signalling with peptide mediators
  • associated with kinase enzyme which phosphorylates other proteins
  • kinase is associated to either the carboxyl domain or a separate protein
55
Q

what do kinase-linked receptors achieve and how fast are they?

A
  • protein phosphorylation leads to control of gene transcription and protein synthesis
  • takes hours
56
Q

what are nuclear receptors?

A
  • intracellular receptors found in cytoplasm or nucleus
  • no transmembrane domains
  • have DNA-binding motifs built into structure to control gene transcription
57
Q

what do nuclear receptors achieve and how fast are they?

A
  • they regulate gene transcription

- take hours

58
Q

what are ligand-gated ion channels (ionotropic)?

A
  • composed of 3-5 protein subunits
  • each subunit has 2-4 transmembrane domains
  • arrangement of domains forms an aqueous pore
  • when an agonist binds to the receptor, it causes the channel to open and allows ions to pass through into the cell
  • channel closes when the agonist is removed or a receptor enters a desensitised state
59
Q

what do ionotropic receptors achieve and how fast are they?

A
  • ions flowing through the pore produce changes in the excitability/potential of the cell
  • fast transmission - milliseconds
  • endogenous agonists are fast/classical small molecule neurotransmitters stored in synaptic vesicles - ACh, GABA, glutamate
60
Q

what happens when ionotropic receptors are activated by excitatory neurotransmitters?

A

PNS = ACh, CNS = glutamate

  • membrane depolarisation
  • AP firing

e. g. Nicotinic ACh receptor nAChR
- at NMJ = muscle contraction
- at autonomic preganglionic neuron = excitation of postganglionic neuron
- brain neurons = reward pathways

agonist = ACh, nicotine, glutamate
antagonist = curare/tubocurarine
61
Q

what happens when ionotropic receptors are activated by inhibitory neurotransmitters?

A
  • cause hyperpolarisation (permeable to anions)
  • reduce AP firing

e. g. GABAa receptor
- inhibit brain interneurons

agonist = GABA, phenobarbitone 
antagonist = picrotoxin - loss of inhibitory transmission in brain
62
Q

what are the subtypes of ionotropic receptors?

A
  1. Cys-loop (pentametric): detemine if Na+ or both Ca2+ and Na+ can enter cell
    - e.g. nAChR, GABAa, 5-HT3
  2. ionotropic glutamate type (iGluRs)(tetrametric): involved in brain development and synaptic plasticity (memory)
    - e.g. NMDA
  3. P2X type (trimeric): mediate fast responses to the transmitter ATP
    - e.g. P2XR
  4. calcium-release type(tetrametric): cause increase in internal calcium
    - e.g. IP3R, RyR
63
Q

what can happen when nicotinic ionotropic receptors malfunction?

A
  • autoimmune disease Myasthenia gravis
  • 1/2000n people
  • muscle weakness
  • issues in NMJ
  • treatment with anticholinesterases to prevent breakdown of ACh:
    • e.g. neostigmine, pyridostigmine
  • treatment with immunosuppressants e.g. prednisolone
64
Q

what are G-protein coupled receptors (GPCRs)?

A
  • 7 transmembrane domains
  • binding domains within amino terminus or a pocket within the membrane
  • intracellular loops are bound to G-proteins which transduce extracellular signals once activated
  • agonist activates G-protein, triggering a signal transduction cascade
  • 800+ mammalian genes encode GPCRs
65
Q

what do GPCRs achieve when activated and how fast are they>

A
  • the triggering of a signal transduction cascade can allow control over function of other proteins e.g. other ion channels, enzymes in the cell
  • they regulate effector proteins via heterotrimeric GTP-binding protein (G-protein)
  • if they control ion channels, they can cause change in voltage across the membrane
  • takes seconds
66
Q

what is an agonist?

A
  • drugs/mediators/ligands that bind to a receptor to produce a response
  • cause a signal transduction e.g. ion channel to open/activate G-protein/activate kinase/activate DNA-binding motif
  • e.g. pilocarpine, nicotine, ACh, morphine
67
Q

what is an antagonist?

A
  • drugs/ligands that prevent/inhibit the action f an agonist
  • they bind to the receptor but do not elicit a response themselves on isolated cells
  • they only produce a response by interfering with an agonist
  • e.g. atropine, curare, naloxone
68
Q

what is a ligand?

A
  • refers to any molecule that binds to the receptor

- can be an agonist or an antagonist

69
Q

what are G-proteins?

A
  • activated G-proteins control functions of effectors e.g. ion channels, enzymes
  • there are 20 types of G-proteins
  • different GPCR subtypes signal via different G-proteins
70
Q

how do G-proteins work?

A
  • neurotransmitter binds to receptor and stabilises it into a structure that is attracted to the G-protein
  • these control downstream effector molecules such as enzymes which are involved in the production of second messengers
71
Q

what is the detailed structure of GPCRs?

A
  • single polypeptide containing 7 transmembrane domains spanning alpha helices
  • two extracellular loops form transmitter binding sites
  • structural variations in loops determine which ligands bind to the receptor
  • two intracellular loops bind and activate G-proteins
  • structural variations in intracellular loops determine which G-protein is activated and which effector systems are activated
72
Q

what subunits are G-proteins composed of?

A
  1. alpha
  2. beta
  3. gamma

both alpha and beta-gamma subunits allow receptors to regulate effectors

73
Q

how are G-proteins switched on?

A
  1. in unstimulated state, receptor and G-protein are inactive, and GDP is associated with alpha in a complex with beta-gamma
  2. when agonist binds, conformational change causes alpha to lower affinity for GDP and increase affinity for GTP
  3. there is an exchange of GDP for GTP, which triggers a conformational change that activates both alpha and beta-gamma
  4. alpha and beta-gamma dissociate to interact with target proteins in plasma membrane
  5. receptor stays active as long as ligand is bound to it
74
Q

how are G-proteins switched off?

A
  1. when alpha interacts with target protein, it activates that protein as long as the two are in contact
  2. alpha hydrolyses its bound GTP to GDP
  3. this causes inactivation of alpha which dissociates from target protein
  4. alpha reassociates with beta-gamma to reform inactive G-protein
  5. G-protein is now ready to be activated again
75
Q

what signal transduction pathways are used by G-proteins?

A
  • enzymes which regulate levels of second messengers

- ion channels

76
Q

what are the 3 cascades used in enzymatic action of G-proteins

A
  1. Gs - stimulatory - activates adenylyl cyclase pathway
    - increases adenylyl cyclase activity which increases cAMP and PKA pathway,
  2. Gq - stimulatory - activates phospholipase C pathway (PLC)
    - increases PLC, increases IP3 and DAG to cause Ca2+ increase
  3. Gi - inhibitory - downregulates adenylyl cyclase pathway
    - decreases adenylyl cyclase activity to decrease cAMP and PKA pathway
77
Q

give two examples of ion channel cascades used by G proteins

A
  1. GIRK - potassium channel is opened by G-protein and causes decreased AP firing
    - opioid receptors - act via Gi protein which increases GIRK opening and decreases Ca2+ influx, decreasing pain transmission in CNS
  2. L-type calcium channels - open by Gs protein when activated by beta1 adrenoreceptor, allowing influx of Ca2+ and causing increased heart rate
78
Q

what is the adenylyl cyclase pathway?

A
  • second messenger cAMP regulates activity of other proteins in signal transduction e.g. PKA, EPAC, CREB

EPAC = nucleotide exchange protein for the Rap subfamily of RAS-like small GTPases

CREB = (cAMP response element binding protein) is a transcription factor which controls gene expression

PKA = (protein kinase A) phosphorylates downstream effectors to regulate their activity

79
Q

describe the PKA process

A

regulated by cAMP by phosphorylating target proteins and regulating their function

example: L-type Ca2+ channels in cardiac muscle activated by adrenalin on beta-1 receptors
1. increase in cAMP by adenylyl cyclase causes increase in PKA
2. increase in phosphorylation of L-type Ca2+ channels
3. causes channel to open and influx of calcium into heart muscle
4. heart contracts more

80
Q

describe phospholipase C activation by GPCRs

A
  • leads to generation of second messengers IP3 and DAG
  • causes increase in intracellular Ca2+ and activation of protein kinase C
  • smooth muscle contraction is stimulated by receptors coupled to Gq and PLC signalling

Physiology and Pharmacology (13 decks)

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