the α4 nicotinic subunit contains a PKC phosphorylation site at Ser-366, and mutation of this site produces receptors that show little recovery from desensitization.206 Interestingly, ethanol can also downregulate nACh receptors, an effect that is attenuated by chelerythrine.207 Chronic nicotine treatment inactivates α4β2 nACh receptors, and this inactivation is mimicked by the PKC inhibitor 2,6-diamino-N-([1-(1-oxotridecyl)-2-piperidinyl] methyl)hexanamide (NPC 15437).208 Prolonged nicotine treatment upregulates homomeric α7 nACh receptors expressed in SH-EP1-hα7 cells, and this upregulation is enhanced by PKCα over-expression; however, upregulation of heteromeric nACh receptors containing α3, α5, α7, β2, and β4 expressed in SH-SY5Y cells is not affected by depletion of PKC.209 These data suggest that PKC is important for recovery from receptor desensitization, receptor inhibition resulting from chronic agonist treatment, and upregulation of homomeric α7 NACh receptors resulting from chronic agonist treatment. Which PKC isozymes mediate these processes is not yet known.
