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5BBM0218 Physiology and Pharmacology of CNS > L5: Second messengers > Flashcards

L5: Second messengers Flashcards

1
Q

What are primary messengers?

A

carry messages between cells

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2
Q

What are secondary messengers?

A

carry messages within the cells

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3
Q

Compare the complexity and speed of primary and secondary messengers

A
  • Second messengers = more complex mechanisms and can activate multiple parallel pathways
  • primary messengers = generally faster
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4
Q

How do second messengers amplify the signal response?

A
  • Second messengers can be synthesized in large quantities as a response to a single primary messenger - leading to signal amplification
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5
Q

How do second messengers show selectivity of response?

A
  • can be active at different times & locations within the cell, allowing for selective responses to specific signals
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6
Q

How can agonists mediate opposite responses via the same second messenger mechanism?

A
  • Agonists can bind to different receptors, leading to different responses via the same second messenger pathway
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7
Q

How can agonists have different effects depending on the tissue they are located in?

A
  • Agonists can bind to the same receptor but have different effects depending on the tissue they are in - influencing the response to the second messenger mechanism
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8
Q

What are the main types of secondary messengers?

A
  • cyclic nucleotides (cAMP and cGMP)
  • molecules derived from lipid bilayers (IP3 and DAG)
  • gases (NO and CO)
  • ions (Calcium)
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9
Q

what are effector enzymes?

A
  • a type of enzyme activated/regulated by a signalling pathway - often involving second messengers or protein kinases
  • play crucial role in transmitting signals within cell & mediating various cellular responses to extracellular stimuli
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10
Q

What are some examples of effector enzymes and their substrates?

A

Adenyl cyclase: ATP → cAMP
Guanylate cyclase: GTP → cGMP
Phospholipase A2: Membrane lipid → Arachidonic acid
Phospholipase C: PIP2 → IP3 and DAG
Nitric oxide synthase: L-arginine → Nitric oxide

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11
Q

What is the function of adenyl cyclase?

A
  • converts ATP to cAMP, which is an important secondary messenger involved in many cellular processes
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12
Q

What is the function of guanylate cyclase?

A

converts GTP to cGMP - critical secondary messenger involved in various cellular responses

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13
Q

What is the role of phospholipase A2?

A
  • Phospholipase A2 hydrolyses membrane lipids to produce arachidonic acid, which is a precursor to many signalling molecules
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14
Q

What does phospholipase C do?

A
  • Phospholipase C cleaves PIP2 to generate IP3 and DAG, both of which are important secondary messengers in signal transduction
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15
Q

What does nitric oxide synthase produce?

A
  • Nitric oxide synthase converts L-arginine to nitric oxide, which is a gaseous signalling molecule with various physiological functions
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16
Q

Which G protein subunit is associated with increasing cAMP levels?

A

Galphas is associated with increasing cAMP levels through activation of adenyl cyclase

17
Q

Which G protein subunit is associated with decreasing cAMP levels?

A

Galphai is associated with decreasing cAMP levels through inhibition of adenyl cyclase

18
Q

Which G protein subunit is associated with increasing IP3 and DAG levels?

A

Galphaq/11 is associated with increasing IP3 and DAG levels by activating phospholipase C

19
Q

What are the two major effects of ligand-gated ion channels?

A
  • allow the entry of calcium ions
  • modify the membrane potential of cells
20
Q

How do tyrosine kinase-linked receptors initiate cellular responses?

A
  • initiate cellular responses by activating effector enzymes & protein kinases through phosphorylation cascades
21
Q

What are the types of target proteins phosphorylated by kinases for long-term changes?

A
  • Kinases phosphorylate target proteins, such as:
  • ion channels
  • transcription factors
  • enzymes, to bring about long-term changes in cellular functions
22
Q

How are the effects of kinases reversed?

A
  • by dephosphorylation of target proteins carried out by phosphatases
23
Q

Which residues do protein kinases primarily target for phosphorylation?

A
  • primarily target serine, threonine, and tyrosine residues for phosphorylation
24
Q

What are the classes of kinases based on their substrate specificity?

A

The classes of kinases include:

  1. Serine/threonine kinases - PKC, PKA, PKG, MAPK, CaMK
  2. Receptor Serine/threonine kinases - TGFß receptor
  3. Dual specificity protein kinases - target tyrosine/threonine residues (e.g., MEK)
  4. Receptor tyrosine kinases - neurotrophic receptors
  5. Non-receptor tyrosine kinases - Src family
25
Q

What is the function of BDNF (Brain-Derived Neurotrophic Factor) in pain processing?

A
  • BDNF alters pain processing by binding to trkB receptors on spinal & peripheral neurons and glia
  • leads to altered gene expression, NMDA receptor activation and trafficking, enhancing the neuronal response to glutamate
26
Q

Describe the activation process of trkB receptors by BDNF

A
  • BDNF binds to trkB receptors, causing conformational change that leads to receptor dimerization
  • intrinsic kinase activity of the receptor is enhanced, resulting in auto-phosphorylation and phosphorylation of other tyrosine residues on the receptor
  • these phosphorylated residues serve as docking sites for signalling proteins
27
Q

What signalling proteins are involved in the trkB receptor pathway?

A
  • trkB receptor pathway involves signalling proteins GRB2 (growth factor receptor-bound protein 2), Sos (guanine nucleotide exchange factor), and Ras (small GTPase)
  • activation of Ras through the Ras-Sos complex leads to activation of the MAP kinase cascade
28
Q

What are the downstream effects of the MAP kinase cascade activation?

A
  • the MAP kinase cascade activation alters gene expression through CREB (cAMP response element-binding protein) & affects other cytosolic targets - leading to diverse cellular responses
29
Q

How does PI-3K (phosphatidylinositol-3 kinase) increase the responsiveness of trkB receptors?

A
  • PI-3K enhances the responsiveness of trkB receptors by increasing the diversity of cellular responses that can be produced with just one molecule of BDNF
30
Q

Where is BDNF synthesized and transported, and what causes an increase in its synthesis?

A
  • BDNF synthesized in primary sensory neurons & transported to their central terminals
  • Its synthesis is increased during local inflammatory processes
31
Q

Describe the signalling cascade involving cAMP and CREB in memory formation

A
  • In memory formation, cAMP and CREB phosphorylation play a role in long-term memory
  • cAMP activates PKA (protein kinase A), and the catalytic subunit of PKA phosphorylates target molecules on serine and threonine residues
  • this cascade modulates memory formation
  • additionally, spatial and temporal localization of this signalling pathway is facilitated by scaffold proteins and A kinase anchoring proteins (AKAPs)
32
Q

What are the major effects of cAMP mediated by PKA?

A
  • involve the dissociation of the regulatory subunit from the catalytic subunit
  • the catalytic subunit then phosphorylates target molecules on serine and threonine residues
  • these target molecules include ion channels, enzymes, and TFs
33
Q

How is AC (adenyl cyclase) involved in signal amplification?

A
  • AC can phosphorylate multiple ATP molecules, resulting in signal amplification
  • it exists in 8 isoforms, and its activation is stimulated by Gas and inhibited by Gai
  • Isoforms I, III, and VIII are activated by calcium/calmodulin, while isoforms V and VI are inhibited by calcium (CaM-independent)
34
Q

What are AKAPs, and what role do they play in signalling cascades?

A
  • AKAPs (A kinase anchoring proteins) are proteins that bind all components of the signalling cascade, forming a small signalling complex near the receptor
  • They play a crucial role in allowing spatial-temporal localization of the signalling pathway
35
Q

How is calcium excitotoxicity avoided in cells?

A
  • Calcium excitotoxicity avoided through various mechanisms that regulate calcium concentration. mechanisms included :
  1. Plasma membrane or smooth endoplasmic reticulum ATPase
  2. Secondary transporters like NCKX (Na in, calcium out, potassium out) or sodium calcium exchanger NCX
  3. Calcium-activated K+ and Cl- channels
  4. Uptake of calcium into cellular compartments (e.g., endoplasmic reticulum, mitochondria) via ATP-dependent mechanisms (e.g., SERCA)
  5. Binding of calcium to Ca2+ buffering proteins (e.g., calbindin, calretinin)
  6. CaM Kinase dependent phosphorylation of Ca2+ channels to decrease their activity
36
Q

How does calcium regulate various processes in cells?

A
  • Ca2+ ions play critical role in regulating a diverse range of processes in cells, including: memory formation, vesicular trafficking & neurogenesis
  • Ca2+ (doesn’t directly bind to most target proteins; instead) binds to calmodulin (CaM), causing conformational change in protein
  • calcium-calmodulin complex then alters activity of other proteins by binding to them & changing their shape
  • many effects of calcium signalling rely on calcium-calmodulin dependent protein kinases (CaMKs), with one of their targets being CREB (which is involved in memory formation)
37
Q

What are the consequences of sustained increases in calcium concentration in cells?

A
  • sustained ↑ in Ca2+ concentration can lead to cell death via necrosis or apoptosis.
  • often a result of ↑ glutamate NMDA receptor activity or decreased cytoplasmic calcium buffering
  • elevated Ca2+ concentrations activate proteases, phospholipases, and endonucleases, which damage the cytoskeleton, cell membrane, and DNA
  • avoiding calcium excitotoxicity is essential to maintain cellular health
38
Q

How does calcium regulation protect cells from calcium excitotoxicity?

A
  • cells utilize various mechanisms to regulate [Ca2+] & prevent Ca2+ excitotoxicity
  • mechanisms include: pumping Ca2+ out of the cell through plasma membrane or smooth endoplasmic reticulum ATPases, secondary transporters, and calcium-activated ion channels
  • Ca2+ is also taken up into cellular compartments, such as the ER and mitochondria, via ATP-dependent mechanisms
  • additionally ca2+ bound to calcium buffering proteins like calbindin and calretinin
  • CaM Kinase can also ↓ the activity of Ca2+ channels through phosphorylation, contributing to calcium regulation & cellular protection

5BBM0218 Physiology and Pharmacology of CNS (17 decks)

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