Protein kinase C deficiency-induced alcohol insensitivity and underlying cellular targets in Drosophila.
Multiple subtypes of protein kinase C (PKC) isozymes are implicated in various neurological disorders including alcohol insensitivity, a trait strongly associated with alcoholism in humans, but molecular and cellular mechanisms underlying the PKC activities remain poorly understood. Here we show that functional knockdown of conventional, novel or atypical PKC in the fly nervous system each resulted in alcohol insensitivity. Neuroanatomical mapping of conventional Ca(2+)-sensitive PKC53E activity uncovers a previously uncharacterized role of Drosophila serotonin neurons in alcohol sensitivity. The deficiency of PKC53E but not novel Ca(2+)-independent PKC98E appears to reduce synaptic serotonin levels, since acute inhibition of serotonin reuptake by citalopram and Prozac reversed alcohol insensitivity in flies expressing PKC53E double-stranded RNA in serotonin neurons. Together, findings from this and our previous studies indicate that PKC53E and PKC98E differentially regulate fly alcohol sensitivity through independent modulation of conserved serotonin and neuropeptide Y-like systems.
Chen
J
J
Department of Cellular Biology and Biomedical and Health Sciences Institute, University of Georgia, 500 DW Brooks Drive, Athens, GA 30602, USA.
Zhang
Y
Y
Shen
P
P
D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004331:Drosophila melanogaster; D004351:Drug Resistance / Q000235:genetics*; D000431:Ethanol / Q000494:pharmacology*; D019143:Evolution, Molecular; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D007527:Isoenzymes / Q000378:metabolism; D009420:Nervous System / Q000187:drug effects* / Q000201:enzymology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D009478:Neuropeptide Y / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics*; D012330:RNA, Double-Stranded / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics
D002492:Central Nervous System Depressants; D000431:Ethanol; D007527:Isoenzymes; D009478:Neuropeptide Y; D011493:Protein Kinase C; D012330:RNA, Double-Stranded; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors