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Functional aspects of neuronal nicotinic receptor diversity

Covernton, Patrick John O'Neill; (1999) Functional aspects of neuronal nicotinic receptor diversity. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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The agonist sensitivity of nicotinic acetylcholine receptors (nAChRs) in rat superior cervical ganglion (SCG) neurones was compared, under voltage-clamp, with that of cloned nicotinic receptor subunit combinations expressed in Xenopus oocytes. Agonist responses in SCG neurones indicated that cytisine was the most potent agonist and lobeline the least potent (Cytisine > DMPP > Nicotine > ACh > Carbachol > Lobeline). The α3β2 combination had a relatively high sensitivity to DMPP and low sensitivity to cytisine (DMPP > ACh > Lobeline > Carbachol > Nicotine > Cytisine). The α3β4 combination had a high sensitivity to cytisine and low sensitivity to DMPP (Cytisine > Nicotine ≈ ACh > DMPP > Carbachol > Lobeline). The results suggest that the nAChRs in the SCG have characteristics of both α3β4 and α3β2 subunit combinations. Complete agonist concentration-response plots were determined for α3β2, α3β4, α4-1β2, α4-1β4 and α7 nAChR subunit combinations. In general, the relationships were poorly fitted by a single component Hill-Langmuir relationship. Improved fits were obtained with the sum of two components, suggesting that pairwise expression of neuronal nicotinic subunits in oocytes may produce more than one functionally distinct receptor. This study also examined the effects of acute ethanol (EtOH) exposure on agonist responses of neuronal nAChRs expressed in oocytes. In some cells, α3β4 responses could be either potentiated or inhibited (25% to 237% of control response) by low EtOH concentrations (1-30mM). At high EtOH concentrations (100-300mM) robust potentiations were observed, (135% to 305%). The α3β2, α4-1β2 and α4-1β4 combinations were less sensitive to low EtOH concentrations, but respectively showed potentiations of up to 178%, 226% and 154% at high concentrations, α7 receptors were also relatively insensitive to low EtOH concentrations, but potentiation or inhibition could be seen at high concentrations (88% to 141%). This modulation may underlie some of the behavioural effects of ethanol. The α3β4 subunit combination may be especially sensitive to modulation by low EtOH concentrations. This remarkable sensitivity and plasticity may contribute to a process of mutual reinforcement in nicotine and alcohol addiction.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Functional aspects of neuronal nicotinic receptor diversity
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Nicotinic acetylcholine receptors
URI: https://discovery.ucl.ac.uk/id/eprint/10120951
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