Peptidyl-prolyl isomerase FKBP52 controls chemotropic guidance of neuronal growth cones via regulation of TRPC1 channel opening.
Immunophilins, including FK506-binding proteins (FKBPs), are protein chaperones with peptidyl-prolyl isomerase (PPIase) activity. Initially identified as pharmacological receptors for immunosuppressants to regulate immune responses via isomerase-independent mechanisms, FKBPs are most highly expressed in the nervous system, where their physiological function as isomerases remains unknown. We demonstrate that FKBP12 and FKBP52 catalyze cis/trans isomerization of regions of TRPC1 implicated in controlling channel opening. FKBP52 mediates stimulus-dependent TRPC1 gating through isomerization, which is required for chemotropic turning of neuronal growth cones to netrin-1 and myelin-associated glycoprotein and for netrin-1/DCC-dependent midline axon guidance of commissural interneurons in the developing spinal cord. By contrast, FKBP12 mediates spontaneous opening of TRPC1 through isomerization and is not required for growth cone responses to netrin-1. Our study demonstrates a novel physiological function of proline isomerases in chemotropic nerve guidance through TRPC1 gating and may have significant implication in clinical applications of immunophilin-related therapeutic drugs.
Shim
Sangwoo
S
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Yuan
Joseph P
JP
Kim
Ju Young
JY
Zeng
Weizhong
W
Huang
Guo
G
Milshteyn
Aleksandr
A
Kern
Dorothee
D
Muallem
Shmuel
S
Ming
Guo-li
GL
Worley
Paul F
PF
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D052837:Chemoautotrophic Growth / Q000502:physiology; D020439:Growth Cones / Q000502:physiology*; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D019696:Peptidylprolyl Isomerase / Q000502:physiology*; D051381:Rats; D050052:TRPC Cation Channels / Q000502:physiology*; D022021:Tacrolimus Binding Proteins / Q000502:physiology*; D014981:Xenopus
D018841:HSP90 Heat-Shock Proteins; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4; D019696:Peptidylprolyl Isomerase