Modulation of serotonin 2C receptor editing by sustained changes in serotonergic neurotransmission.
Serotonin 2C (5-HT2C) receptor pre-mRNA is a substrate for RNA editing enzymes that convert five adenosines (named A, B, C', C, and D editing sites) to inosines. Editing of two of these sites (C' and C) is crucial for decreasing the efficiency of the receptor to activate G-protein. Nucleotide sequence analysis of mouse forebrain neocortical 5-HT2C mRNA isoforms revealed that editing at these two sites is regulated in a serotonin-dependent manner. In serotonin-depleted mice, C'- and C-site editing is significantly decreased. This results in an increased expression of 5-HT2C mRNA isoforms encoding receptors with higher sensitivity to serotonin. In contrast, a 4 d treatment with the 5-HT2A/2C agonist (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane significantly increases the editing frequency at the C' site and leads to increased expression of 5-HT2C mRNA isoforms encoding receptors that activate G-protein least efficiently. None of the drug treatments led to alterations in cytoplasmic 5-HT2C mRNA levels. These data indicate that editing of 5-HT2C pre-mRNA is a mechanism that retains basic response properties of 5-HT2C receptors in the face of changing synaptic input to keep receptor activation within an optimal range for information processing. Key words: serotonin; 5.
Gurevich
Ilona
I
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Englander
Michael T
MT
Adlersberg
Mella
M
Siegal
Nathan B
NB
Schmauss
Claudia
C
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D003593:Cytoplasm / Q000235:genetics; D010134:Fenclonine / Q000494:pharmacology; D008297:Male; D051379:Mice; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism*; D017393:RNA Editing; D012322:RNA Precursors / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis*; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000235:genetics* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D000662:Amphetamines; D012322:RNA Precursors; D012333:RNA, Messenger; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D010134:Fenclonine