The serotonin transporter (SERT) is a major regulator of serotonergic neurotransmission and anxiety-related behaviors. SERT is expressed in two alternative polyadenylation forms that differ by an evolutionarily conserved element in the 3′ untranslated region of its mRNA. Expression of SERT mRNA containing the distal polyadenylation element is associated with decreased anxiety-related behaviors in mice and humans, suggesting that this element has behaviorally relevant modulatory effects on SERT expression. We have identified heterogeneous nuclear ribonucleoprotein K (hnRNPK), a protein known to integrate multiple signal transduction pathways with gene expression, as a SERT distal polyadenylation element binding protein. This interaction is functionally meaningful because genetic manipulation of hnRNPK alters expression of the SERT protein. Furthermore, the trophic factor S100β induces Srcfamily kinase-mediated tyrosine phosphorylation of hnRNPK and increased SERT expression. These results identify a previously unknown mechanism of regulated SERT expression and provide a putative mechanism by which the SERT distal polyadenylation element modulates anxiety-related behaviors.A lternative polyadenylation creates structural and functional diversity in the expression of protein coding messenger RNA (mRNA) through the formation of mRNA species that differ in the sequence content of their 3′ untranslated regions (UTRs) (1-3). The 3′ UTRs of mRNAs have become recognized as major sources of regulated gene expression through sequence-specific microRNA (miR) and ribonucleoprotein (RNP) binding that can alter the stability, translational activity, and subcellular localization of mRNAs (4-6). As a result, alternative polyadenylation forms of mRNA species may display discrete biological properties (7,8).The serotonin transporter (SERT; SLC6A4) plays a central role in regulating serotonergic neurotransmission, and the mRNA coding for SERT occurs in two phylogenetically conserved alternative polyadenylation forms that differ by the presence or absence of an ∼125-bp element (9, 10). We have reported that expression of the longer, or distal, polyadenylation form of the SERT mRNA confers anxiolytic properties on behavior (11, 12). Specifically, males express higher levels of the distal polyadenylation form of SERT than females, who display a two-to threefold higher risk for anxiety disorders than males; a common polymorphism that is associated with expression of the SERT polyadenylation forms in human postmortem brain is also associated with risk for panic disorder, trait anxiety, and the ability of human subjects to retain fear extinction learning, a validated endophenotype of anxiety and its disorders (11,12). Finally, treatment of mice with the SERTselective antidepressant/anxiolytic drug fluoxetine, which has also been shown to enhance fear extinction retention, increases expression of the distal polyadenylation form of SERT (12,13).To advance understanding of how the SERT distal polyadenylation sequence modulates anxiety-relate...