Ephrins & Pain Flashcards
Research paper that discusses topics of the lecture: https://www.nature.com/articles/nn1034
What are EphB receptors?
- Cell membrane proteins
- Belong to the largest subfamily of receptor protein-tyrosine kinase
- they bind to bind to ephrinB1-B3, which are transmembrane molecules.
- Crucial in embryonic development processes.
What are ephrins?
- Ligands for EphB receptors.
- Also membrane-bound proteins.
- Activate EphB receptors through cell-to-cell interactions.
What are the two types of EphB receptors, and what do they bind to?
EphA’s and EphB’s.
EphA’s bind to ephrinA1-5 (GPI anchor).
EphB’s bind to ephrinB1-B3 (transmembrane).
Do EphB receptors have specific antagonists and agonists?
- EphB receptors do not have specific antagonists or agonists.
- They are promiscuous in binding to ligands with varying affinities.
How is IgG used in regulating EphB receptors?
-Fc region of IgG attached to EphB receptors.
- Forms chimeric molecules
- Acts as an antagonist by preventing ephrin binding.
Can chimeric molecules be created for ephrins as well?
- Yes, chimeric molecules can be made with ephrinB and IgG Fc.
- Acts as an agonist, but lacks specificity for target receptors.
What are the effects of ephrinB2 on pain sensitivity in rats, and what does this suggest?
- EphrinB2 induces long-term structural changes in neurons
- Causes rapid hyperalgesia, implying involvement in central sensitization
How do EphB receptors affect pain behaviour modulation?
- EphB receptors act as agonists or antagonists
- Involved in thermal hyperalgesia, mechanical allodynia, and neuropathic pain
What is the role of EphrinB activation in chronic pain, both in onset and maintenance?
- EphrinB activation plays a crucial role in both the onset & maintenance of chronic pain.
- can rapidly increase pain sensitivity in DH of the spinal cord
How are NMDA receptors related to EphrinB2-induced hyperalgesia?
- NMDA receptors are involved in chronic pain induction.
- Blocking NMDA receptors with MK801 can prevent the hyperalgesic effects of EphrinB2.
How does EphB receptor activation rapidly increase responses in DH neurons?
- EphB receptor activation increases synaptic strength by recruiting the non-receptor tyrosine kinase src.
- Src phosphorylates NMDA receptor subunit NR2B, enhancing channel open probability and Ca influx.
What activates ephrinB2 in nociceptive neurons and how does it affect pain?
- EphrinB2 is constitutively expressed but activated by strong stimuli, inflammation, or nerve injury.
- Activation leads to pain sensitization by recruiting more ephrinB2 to the cell membrane
How are EphB receptors and ephrins altered in models of chronic pain?
- They interact more in chronic pain models
- More ephrinB2 is expressed in the presynaptic membrane, leading to EphB1 receptor activation and downstream effects
Are EphB-ephrinB interactions involved in microglial activation?
- EphB-ephrinB interactions may not activate microglia.
- In ephB1 receptor KO mice, there is reduced activation of microglia.
Do EphB receptors exist on peripheral terminals, and what role might they play?
- EphB receptors exist on peripheral terminals but their activation triggers are unknown.
- Their role in pain onset & effects on central or peripheral receptors need further study
What are the various mechanisms that can produce pain?
nociception, inflammation, nerve damage, peripheral and central sensitization, ectopic excitability & decreased inhibition.
How do ephrins and Eph receptors interact, and what type of complex is formed?
- Ephrin-Eph interaction requires cell-to-cell contact and results in the formation of a tetrameric complex.
- Each ligand interacts with two receptors, and each receptor interacts with two ligands
What evidence suggests the involvement of ephrins and Eph receptors in pain modulation?
- that ephrins and Eph receptors are involved in the modulation of different types of pain.
How are ionotropic NMDA receptors related to nociceptive signaling and chronic pain development?
- Ionotropic NMDA receptors play a significant role in nociceptive signaling and are implicated in the primary mechanisms for the development of chronic pain through central sensitization
What happens when C fibers fire for an extended period, and how does it relate to sensitization?
-Prolonged firing of C fibers leads to the release of glutamate, which activates NMDA receptors in the spinal cord.
- Activation of these receptors makes spinal cord neurons more responsive to all inputs, resulting in sensitization.
