Sustained nicotine exposure differentially affects alpha 3 beta 2 and alpha 4 beta 2 neuronal nicotinic receptors expressed in Xenopus oocytes.
To determine whether prolonged exposure to nicotine differentially affects alpha 3 beta 2 versus alpha 4 beta 2 nicotinic receptors expressed in Xenopus oocytes, oocytes were coinjected with subunit cRNAs, and peak responses to agonist, evoked by 0.7 or 7 microM nicotine for alpha 4 beta 2 and alpha 3 beta 2 receptors, respectively, were determined before and following incubation for up to 48 h with nanomolar concentrations of nicotine. Agonist responses of alpha 4 beta 2 receptors decreased in a concentration-dependent manner with IC50 values in the 10 nM range following incubation for 24 h and in the 1 nM range following incubation for 48 h. In contrast, responses of alpha 3 beta 2 receptors following incubation for 24-48 h with 1,000 nM nicotine decreased by only 50-60%, and total ablation of responses could not be achieved. Attenuation of responses occurred within the first 5 min of nicotine exposure and was a first-order process for both subtypes; half-lives for inactivation were 4.09 and 2.36 min for alpha 4 beta 2 and alpha 3 beta 2 receptors, respectively. Recovery was also first-order for both subtypes; half-lives for recovery were 21 and 7.5 h for alpha 4 beta 2 and alpha 3 beta 2 receptors, respectively. Thus, the responsiveness of both receptors decreased following sustained exposure to nicotine, but alpha 4 beta 2 receptors recovered much slower. Results may explain the differential effect of sustained nicotine exposure on nicotinic receptor-mediated neurotransmitter release.
Hsu
Y N
YN
Department of Pharmacology and Therapeutics, University of South Florida College of Medicine, Tampa 33612-4799, USA.
Amin
J
J
Weiss
D S
DS
Wecker
L
L
D000818:Animals; D004553:Electric Conductivity; D005071:Evoked Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism; D009994:Osmolar Concentration; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014982:Xenopus laevis
D018377:Neurotransmitter Agents; D011978:Receptors, Nicotinic; D009538:Nicotine