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LF260 Neuropharmacology > Lecture 9: Purinergic Signaling > Flashcards

Lecture 9: Purinergic Signaling Flashcards

1
Q

What is a purine?

A

Heterocyclic aromatic organic compound composed of a pyrimidine ring fused with an imidazole ring.

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2
Q

What is the role of adenine in purine signaling?

A
  • Component of purine nucleotides and nucleosides and plays a role in purine signaling.
  • Acts on P0 receptors.
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3
Q

What is theobromine, and where is it commonly found?

A

Purine alkaloid that is commonly found in chocolate.

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4
Q

Name two adenine nucleotide signaling molecules.

A
  • ATP (adenosine triphosphate)
  • ADP (adenosine diphosphate)
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5
Q

What are adenine nucleoside signaling molecules? Provide an example.

A
  • Compounds composed of adenine linked to a ribose sugar.
  • Example: adenosine
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6
Q

What is unusual about transmitter ATP?

A
  • Transmitter ATP is sequestered into vesicles and has its own transporter called VNUT (vesicular nucleotide transporter).
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7
Q

Describe the process of ATP release and its storage.

A
  • ATP is stored inside vesicles and released by exocytosis.
  • It can be released either as a co-transmitter with other neurotransmitter molecules or on its own.
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8
Q

How does ATP activate receptors?

A

ATP can activate receptors such as P2X receptors (ligand-gated ion channels) and P2Y receptors (G-protein coupled receptors).

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9
Q

What happens to ATP in the extracellular space?

A

ATP is metabolized by nucleotidases (enzymes), which limits its signaling and gives rise to other signaling molecules.

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10
Q

Describe the conversion of ATP to ADP and adenosine.

A

ATP can be converted to ADP, which activates P2Y receptors, and further to adenosine, which activates P1 receptors.

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11
Q

What is an accumulative transporter, and how does it work for adenosine?

A
  • Accumulative transporter: transporter that removes adenosine from the extracellular space.
  • It works by maintaining a concentration gradient, allowing adenosine to accumulate outside the cell and then be transported inside when the concentration inside the cell is high.
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12
Q

How is the concentration gradient of adenosine maintained?

A

Maintained through adenosine kinase, which phosphorylates adenosine to AMP, reducing the concentration of adenosine inside the cell and promoting its uptake from the extracellular space.

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13
Q

How many subtypes of P2Y receptors are there?

A

8 subtypes

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14
Q

Which P2Y receptors are activated by ATP?

A

P2Y2 and P2Y11

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15
Q

Which signaling molecules activate P2Y receptors?

A

Other signaling molecules, particularly ADP

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16
Q

How does adenosine activate its receptors?

A

G protein-coupled receptors (GPCRs) belonging to the P1 family, which has 3 subtypes.

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17
Q

What evidence supports ATP as a neurotransmitter?

A
  • Nerve stimulation experiments have shown that adding alpha beta methylene-ATP desensitizes P2X receptors → a smaller response, indicating that activation is mediated by these receptors.
  • Additionally, spontaneous release of individual vesicles containing ATP has been observed.
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18
Q

What types of vesicles contain ATP?

A

Large granular vesicles (SGV) containing neuropeptides, as well as SGV containing classical neurotransmitters like noradrenaline, have been found to contain ATP.

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19
Q

How does ATP influence neurotransmission and tissue properties?

A

Excitation and the modulation of activity through negative feedback mechanisms, such as the adenosine switch-off release of synapse.

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20
Q

How does stimulating purinergic nerves affect activity?

A

Inhibition of activity in some tissues, as observed in the example of Taenia coli, where nerve stimulation inhibits spontaneous activity, hyperpolarizes membranes to prevent action potentials from firing, and can lead to either contraction or inhibition depending on the tissue and receptor involved.

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21
Q

What is the effect of PPADS on P2X receptors?

A

Blocks P2X receptors and leads to a strong depression of synaptic transmission.

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22
Q

How was the identification of P2X-mediated synaptic transmission in the brain achieved?

A

Recordings were made from the medial habenula pathway, and synaptic transmission in the medial habenula was identified as not being nicotinic (not blocked by hexamethonium). In the medial habenula, synaptic transmission mediated by P2X receptors was observed.

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23
Q

What is the effect of PPADS on synaptic transmission mediated by ATP-activated P2X receptors in the CNS?

A

PPADS blocks P2X receptors → strong depression of synaptic transmission mediated by ATP-activated P2X receptors in the CNS.

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24
Q

Describe the structure of the nicotinic receptor superfamily

A

Single polypeptide chains that form a pentameric structure

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25
Q

Describe the structure of the ATP P2X receptor family.

A

The ATP P2X receptor family is trimeric, with each receptor having two transmembrane domains.
The TM2 region is replicated across each of these receptors, making TM2 a core feature.

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26
Q

Describe the structure of the glutamate receptor family.

A

Tetrameric and includes receptors such as AMPAR, NMDAR, and KARs.

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27
Q

Does this receptor behave similarly to other receptors in terms of allowing ions to flow through?

A

Yes, the receptor allows ions to flow through, but it has unique structural features that influence ion flow dynamics.

28
Q

How is the nicotinic receptor different from other receptors?

A

The nicotinic receptor has an intracellular vestibule that requires ions to flow laterally out of the channel. This mechanism is similar to the P2X receptor but is oriented upside down.

29
Q

What did Samways et al. conclude about the ion path of the P2X receptor?

A

Ion path is close to the membrane of the cell, and ions flow from the lower regions into the channel. This conclusion was reached through mutation experiments.

30
Q

How is purinergic signaling involved in pain pathways?

A
  • Purinergic signaling can be seen in pain pathways, where ATP signaling occurs at various points.
  • ATP released in response to stimuli activates sensory nerve endings, indicating injury or damage.
31
Q

How can analgesia be achieved through P2X and A1 agonists?

A
  • Agonists of P2X and A1 receptors can induce analgesia.
  • ATP released at sensory nerve endings in response to injury or damage stimulates these receptors, modulating pain perception.
32
Q

What are some sources of ATP release associated with pain?

A
  • Tumor cells, cancers, endothelial cells, and Merkel cells
  • ATP release from these cells signals damage or noxious stimuli to sensory nerve endings.
33
Q

How does ATP contribute to pain-killing mechanisms through conversion to adenosine?

A

ATP can be converted to adenosine, which activates A1 receptors to provide pain-killing properties. This evolutionary mechanism helps invoke pain-killing mechanisms to fend off danger.

34
Q

How does the release of ATP contribute to the coughing reflex?

A
  • Irritation or damage to tissues lining the airways leads to the release of ATP.
  • ATP activates P2X3 receptors on nerve fibers, triggering the coughing reflex.
35
Q

What were the findings of The Lancet Study regarding P2X3 receptor agonists and cough frequency?

A

In the placebo group, there was no change in cough frequency. However, treatment with a P2X3 receptor agonist (now known as Gefapixant) resulted in a dramatic decrease in cough frequency.

36
Q

How is the P2X7 receptor activated, and what are its implications in CNS conditions?

A
  • The P2X7 receptor is activated by high concentrations of ATP, typically seen in conditions involving tissue damage in the CNS. Under normal circumstances, it is activated by ATP to produce a low level of signaling.
  • However, changes in receptor properties or associated proteins can lead to excessive influxes of sodium and calcium ions, causing cellular damage.
37
Q

What were the results of the Crohn’s disease study involving P2X7 antagonists?

A
  • Reported less pain and improvement in well-being compared to those on a placebo.
  • This suggests a potential therapeutic benefit of P2X7 antagonists in managing Crohn’s disease symptoms.
38
Q

What distinguishes P2X7 receptors from other receptors regarding desensitization?

A

P2X7 receptors, when activated, do not undergo desensitization. They continue to conduct ions, which can be damaging to cells over time.

39
Q

What factor influences the desensitization of P2X7 receptors?

A
  • The presence of palmitoylation
  • Palmitoylation prevents desensitization, keeping the receptor in an open state.
40
Q

How does platelet aggregation relate to wound healing and homeostasis?

A
  • Platelet aggregation is essential for wound healing and maintaining homeostasis.
  • When there is tissue injury, platelets aggregate at the site to form a plug, preventing excessive bleeding and promoting the initiation of the healing process.
41
Q

What is the significance of thrombi formation in atherosclerosis?

A
  • In atherosclerosis, thrombi formation can occur, leading to the formation of blood clots that can occlude blood vessels.
  • This occlusion deprives tissues of adequate blood supply and can lead to serious complications such as strokes if the thrombi break off and travel through the bloodstream.
42
Q

How do antagonists of P2Y12 receptors impact atherosclerosis?

A

Antagonists of P2Y12 receptors inhibit platelet aggregation, reducing the risk of adverse events associated with atherosclerosis attacks such as thrombosis.

43
Q

What is the significance of designing drugs targeting different receptors in the heart?

A
  • Designing drugs that target different receptors in the heart allows for the modulation of various physiological processes.
  • For example, the heart contains adenosine receptors that play roles in dilating blood vessels and regulating energy demand.
44
Q

What protective functions are associated with adenosine receptors in the heart?

A
  • Adenosine receptors in the heart perform various protective functions, including dilating blood vessels and regulating energy demand.
  • Additionally, adenosine accumulation can slow down the heart rate, particularly during periods of increased cardiac activity to prevent excessive strain on the heart.
45
Q

How are adenosine receptors used therapeutically in heart rhythm management?

A
  • To restore normal heart rhythm in cases of supraventricular tachycardia, where the heart beats quickly and irregularly.
  • By injecting adenosine, the abnormal rhythm can be converted back to a normal sinus rhythm.
46
Q

What happens when adenosine is injected during supraventricular tachycardia?

A
  • Injection of adenosine during supraventricular tachycardia results in the restoration of the heart’s normal rhythm.
  • This helps to synchronize and coordinate the heart rate, resolving the irregular and uncoordinated heartbeat associated with supraventricular tachycardia.
47
Q

What did the study by During & Spencer in 1992 reveal about adenosine levels during seizures?

A
  • The study measured adenosine release during seizures using microanalysis and found high levels of adenosine in epileptic tissue during seizures.
  • These elevated levels persisted for some time and were associated with the suppression of further epileptic activity.
48
Q

How does adenosine affect epileptic activity during seizures?

A
  • High levels of adenosine released during seizures suppress further epileptic activity.
  • This suggests that adenosine plays a regulatory role in modulating seizure activity and may serve as a protective mechanism against excessive neuronal firing.
49
Q

What happens when individuals are exposed to convulsant solutions?

A
  • Exposure to convulsant solutions triggers seizure activity, accompanied by a high level of adenosine release under these conditions.
  • This suggests a response to the increased demand for adenosine during seizure events.
50
Q

Why is adenosine considered to be the signaling molecule rather than ATP during seizures?

A
  • Adenosine, rather than ATP, is believed to be the signaling molecule during seizures because ATP sensors do not detect any signal.
  • This indicates that ATP is likely being rapidly converted to adenosine within the cells, which is then released to exert its effects on neuronal activity.
51
Q

How does adenosine affect seizure activity in control conditions?

A

Supresses seizure activity in control conditions, indicating its role in regulating neuronal excitability.

52
Q

What happens when antagonists of A1 receptors are administered during seizures?

A

Longer seizures, suggesting that activation of A1 receptors by adenosine plays a role in limiting seizure duration.

53
Q

What is the effect of CPT (Chemical Convulsant Penicillin) on seizure activity?

A
  • CPT turns normal healthy tissue into tissue exhibiting spontaneous seizure activity.
  • Seizures induced by CPT become longer and more intense, highlighting the role of adenosine in regulating seizure activity.
54
Q

How is adenosine’s ability to regulate seizure activity exploited in electric convulsion therapy (ECT)?

A

Adenosine’s ability to regulate seizure activity is utilized in ECT, where its release is promoted to induce depression of synaptic transmission and mitigate seizure activity.

55
Q

What role does adenosine kinase play in regulating adenosine levels in the extracellular space (EC)?

A

Adenosine kinase is an important regulator of the amount of adenosine in the EC space. Inhibiting adenosine kinase leads to an increase in extracellular adenosine levels.

56
Q

What effect does poisoning adenosine kinase with ADO have on synaptic transmission?

A
  • Poisoning adenosine kinase with ADO → more adenosine remaining outside the cell, leading to depression of synaptic transmission.
  • This underscores the role of adenosine in modulating synaptic activity and its potential therapeutic implications in conditions such as seizures.
57
Q

Where is adenosine kinase predominantly located?

A

Adenosine kinase is predominantly located in astrocytes.

58
Q

How does severe epilepsy affect astrocytes and adenosine kinase levels?

A

Proliferation of astrocytes → increased expression of astrocytes (astrocytosis) and consequently higher levels of adenosine kinase.

59
Q

Describe the experimental model used to study the relationship between seizures and adenosine kinase expression.

A

In the experimental model, seizures are induced by administering kainic acid. Following kainic acid treatment, there is a high level of expression of astrocytes (astrocytosis), resulting in an increase in adenosine kinase (ADK) levels.

60
Q

What is the implication of increased adenosine kinase expression in epilepsy?

A
  • Disrupts the normal mechanism to regulate adenosine levels.
  • This leads to more of the enzyme responsible for removing adenosine from the synaptic cleft → lower levels of adenosine in the synapses.
  • Lowers the threshold for seizure initiation.
61
Q

What are the effects of higher levels of adenosine on seizure activity?

A
  • Animals with higher levels of adenosine are protected from seizure activity.
  • This protection can be reversed by using an A1 receptor antagonist, indicating that the reduced seizure activity is entirely due to the accumulation of adenosine.
62
Q

What happens when adenosine kinase (ADK) levels are genetically increased in mice?

A

When adenosine kinase levels are genetically increased in mice, seizures become fatal.

63
Q

Describe the experimental setup for recording electrical activity in the hippocampus after kainate administration.

A

Electrical activity in the hippocampus is recorded after administering kainate, a convulsant, to induce seizures.

64
Q

What is the effect of administering 5’-iodo-tubercidin on seizure activity, and how does it work?

A
  • Strongly suppresses seizure activity
  • Suppression is attributed to the accumulation of adenosine caused by the poisoning of the adenosine kinase (ADK) enzyme.
65
Q

How do animals with deficiency in ADK enzyme respond to kainate-induced seizures compared to wild-type (WT) animals?

A

Animals with deficiency in the ADK enzyme show protection from seizure activity, likely due to the accumulation of adenosine and subsequent adenosine receptor activation.

66
Q

What is the consequence of genetic increase in ADK levels?

A

Genetic increase in ADK levels leads to a decrease in adenosine levels and results in lethal seizures.

LF260 Neuropharmacology (14 decks)

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