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J. Biol. Chem., Vol. 278, Issue 42, 40744-40748, October 17, 2003

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Ca²⁺-dependent Regulation of TrkB Expression in Neurons^*

Tami J. Kingsbury, Recipient of postdoctoral fellowship support from the American Heart Association, Maryland Affiliate, and the National Institutes of Health (5T32NS07375). , Peter D. Murray , Linda L. Bambrick ¶ and Bruce K. Krueger

From the Departments of Physiology and ^¶Anesthesiology and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201

The neurotrophin brain-derived neurotrophic factor (BDNF), via activation of its receptor, tyrosine receptor kinase B (trkB), regulates a wide variety of cellular processes in the nervous system, including neuron survival and synaptic plasticity. Although the expression of BDNF is known to be Ca²⁺-dependent, the regulation of trkB expression has not been extensively studied. Here we report that depolarization of cultured mouse cortical neurons increased the expression of the full-length, catalytically active isoform of trkB without affecting expression of the truncated isoform. This increase in protein expression was accompanied by increased levels of transcripts encoding full-length, but not truncated, trkB. Depolarization also regulated transcription of the gene, TRKB, via entry of Ca²⁺ through voltage-gated Ca²⁺ channels and subsequent activation of Ca²⁺-responsive elements in the two TRKB promoters. Using transient transfection of neurons with TRKB promoter-luciferase constructs, we found that Ca²⁺ inhibited the upstream promoter P1 but activated the downstream promoter P2. Ca²⁺-dependent stimulation of TRKB expression requires two adjacent, non-identical CRE sites located within P2. The coordinated regulation of BDNF and trkB by Ca²⁺ may play a role in activity-dependent survival and synaptic plasticity by enhancing BDNF signaling in electrically active neurons.

Received for publication, March 25, 2003 , and in revised form, July 31, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY307416.

^* This work was supported by grants from the National Institutes of Health (AG10686, NS40492) and the U.S. Army Medical Research and Materiel Command (Neurotoxin Initiative; DAMD17-99-1-9483). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by National Institutes of Health Training Grant 2T32GM08181.

To whom correspondence should be addressed: Dept. of Physiology, University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD 21201. Tel.: 410-706-2667; Fax: 410-706-8341; E-mail: tking001{at}umaryland.edu.

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