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The Journal of Neuroscience, June 11, 2008, 28(24):6196-6201; doi:10.1523/JNEUROSCI.0443-08.2008

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Brief Communications
Developmental Modulation of GABA_A Receptor Function by RNA Editing

Elizabeth Y. Rula,^1 * Andre H. Lagrange,^2 * Michelle M. Jacobs,⁴ NingNing Hu,² Robert L. Macdonald,^1,2,3,4 and Ronald B. Emeson^1,3,4

Departments of ¹Pharmacology, ²Neurology, and ³Molecular Physiology and Biophysics, and ⁴Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee 37232

Correspondence should be addressed to Dr. Andre H. Lagrange, Vanderbilt University Medical Center, 6140 Medical Research Building III, 465 21st Avenue, South, Nashville, TN 37232-8552. Email: andre.h.lagrange{at}vanderbilt.edu

Adenosine-to-inosine (A-to-I) editing of RNA transcripts is an increasingly recognized cellular strategy to modulate the function of proteins involved in neuronal excitability. We have characterized the editing of transcripts encoding the 3 subunit of heteromeric GABA_A receptors (Gabra3), in which a genomically encoded isoleucine codon (ATA) is converted to a methionine codon (ATI) in a region encoding the predicted third transmembrane domain of this subunit. Editing at this position (I/M site) was regulated in a spatiotemporal manner with 90% of the Gabra3 transcripts edited in most regions of adult mouse brain, but with lower levels of editing in the hippocampus. Editing was low in whole-mouse brain at embryonic day 15 and increased during development, reaching maximal levels by postnatal day 7. GABA-evoked current in transfected cells expressing nonedited 3(I)β32L GABA_A receptors activated more rapidly and deactivated much more slowly than edited 3(M)β32L receptors. Furthermore, currents from nonedited 3(I)β32L receptors were strongly outwardly rectifying (corresponding to chloride ion influx), whereas currents from edited 3(M)β32L receptors had a more linear current/voltage relationship. These studies suggest that increased expression of the nonedited 3(I) subunit during brain development, when GABA is depolarizing, may allow the robust excitatory responses that are critical for normal synapse formation. However, the strong chloride ion influx conducted by receptors containing the nonedited 3(I) subunit could act as a shunt to prevent excessive excitation, providing the delicate balance necessary for normal neuronal development.

Key words: GABA_A receptors; ion channel structure–function; binding–gating transduction; kinetics; development; synaptogenesis

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Received Jan. 31, 2008; revised April 19, 2008; accepted May 6, 2008.

Correspondence should be addressed to Dr. Andre H. Lagrange, Vanderbilt University Medical Center, 6140 Medical Research Building III, 465 21st Avenue, South, Nashville, TN 37232-8552. Email: andre.h.lagrange{at}vanderbilt.edu

This article has been cited by other articles:

				Y. Kawahara, M. Megraw, E. Kreider, H. Iizasa, L. Valente, A. G. Hatzigeorgiou, and K. Nishikura Frequency and fate of microRNA editing in human brain Nucleic Acids Res., August 6, 2008; (2008) gkn479v1. [Abstract] [Full Text] [PDF]

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