PEX5R (also called TRIP8b, tetratricopetide repeat-containing Rab8b-interacting protein) is a cytoplasmic protein expressed as a family of alternatively spliced isoforms. PEX5R /TRIP8b isoforms contain a large constant domain preceded by a variable region. The C-terminal half of TRIP8b comprises a tetratricopeptide repeat (TPR) protein binding domain. Analysis of the Pex5p-like protein revealed the presence of a tetratricopeptide repeat (TPR) domain in its C-terminal half consisting of seven TPR motifs. Pex5R is almost exclusively expressed in brain. Recent studies provide strong evidence that PEX5R interacts with the carboxyl-terminal region of Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and regulates their cell-surface expression level and cyclic nucleotide dependence. HCN channels are key modulators of neuronal activity by providing the depolarizing cation current involved in rhythmogenesis, dendritic integration, and synaptic transmission. In contrast, Gosh et al. have shown that human PEX5R can bind to peroxisomal targeting signal-1 (PTS1) ligands. Furthermore it was shown that enzyme alanine–glyoxylate aminotransferase (AGT) is recognized by PEX5R in the cytoplasm, which allows its subsequent translocation into the peroxisome. TRIP8b may play a role in both normal neuronal function and in aberrant neuronal excitability associated with neurological diseases.