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Title: The role of Gq protein-coupled receptors and SK channels in synaptic NMDA receptor function
Author: Olivo , Valeria
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2013
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SK channels are activated by a rise in intracellular [Ca2+] and are expressed in the postsynaptic density of dendritic spines of CAl pyramidal neurons in the hippocampus, where they are activated by Ca2+ influx through both NMDA receptors (NMDARs) and voltage-gated Ca channels. Activation of SK channels hyperpolarises spines, reducing the amplitude of EPSPs, and therefore increasing the Mg2+ block of NMDARs and the threshold for long-term potentiation (LTP) induction, It has been shown that activation of M1 muscarinic acethylcholine receptors enhances the NMDAR-mediated component of EPSPs by inhibiting of SK channels in a PKC-dependent manner. This study investigates the possibility that other Gq protein-coupled receptors in CAl pyramidal cells could inhibit SK channels by similar molecular pathways and thereby facilitate synaptic NMDAR function. Firstly, it was confirmed that muscarinic M1 receptor activation enhanced the NMDAR-mediated component of EPSPs by inhibiting SK2 channels in a PKCdependent manner. Subseq"uently, the ability of Gq protein-coupled metabotropic glutamate receptors to inhibit SK channels was examined. Activation of mGluRl receptors by DHPG enhanced the NMDAR-mediated component of EPSPs through inhibition of SK channels in a similar fashion to M1 receptors, but interestingly this occured in a PKC-independent manner. Finally, it was tested whether Gq coupled dopamine receptors could inhibit SK channels and enhance the NMDAR-mediated component of EPSPs. The putative D1-D2 heteromeric dopamine receptor agonist SKF83959 strongly inhibited SK channels and enhanced the NMDAR-mediated component of EPSPs. However, these effects were not blocked by D1 or D2 dopamine receptor antagonists and furthermore a broad spectrum dopamine reteptor agonist did not replicate the effect of SKF83959. These results are more consistent with an effect of . SKF83959 on SK channels that is independent of dopamine receptors.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available