Intracellular Fibroblast Growth Factor 14: Emerging Risk Factor for Brain Disorders

Abstract

The finely tuned regulation of neuronal firing relies on the integrity of ion channel macromolecular complexes. Minimal disturbances of these tightly regulated networks can lead to persistent maladaptive plasticity of brain circuitry. The intracellular fibroblast growth factor 14 (FGF14) belongs to the nexus of proteins interacting with voltage-gated Na+ (Na_v) channels at the axonal initial segment. Through isoform-specific interactions with the intracellular C-terminal tail of neuronal Na_v channels (Na_v1.1, Na_v1.2, Na_v1.6), FGF14 controls channel gating, axonal targeting and phosphorylation in neurons effecting excitability. FGF14 has been also involved in synaptic transmission, plasticity and neurogenesis in the cortico-mesolimbic circuit with cognitive and affective behavioral outcomes. In translational studies, interest in FGF14 continues to rise with a growing list of associative links to diseases of the cognitive and affective domains such as neurodegeneration, depression, anxiety, addictive behaviors and recently schizophrenia, suggesting its role as a converging node in the etiology of complex brain disorders. Yet, a full understanding of FGF14 function in neurons is far from being complete and likely to involve other functions unrelated to the direct regulation of Na_v channels. The goal of this Mini Review article is to provide a summary of studies on the emerging role of FGF14 in complex brain disorders.

Keywords: biological psychiatry; intracellular signaling; neuronal excitability; protein-protein interactions.

Figure 1

Known functions of amino acids in fibroblast 14 (FGF14). (A) Alignment of wild-type FGF14-1a and FGF14-1b protein sequences with highlighted residues representing surface hot-spots for FGF14:Na_v1.6 interactions (green, Ali et al., 2016), casein kinase II (CK-2) phosphorylation sites (yellow, Hsu et al., 2016), and the spinocerebellar ataxia 27 (SCA27) F145S mutation site (red, Laezza et al., 2007). (B) An FGF14 homology model generated using the FGF13:Na_v1.5 crystal structure (Protein Data Bank ID: 4DCK) as template, visualized using the visual molecular dynamic (VMD) software package (Humphrey et al., 1996). Surface hot-spots important for protein:protein interactions (green) and the SCA27 F145S mutation (red) are shown.