Neurotrophic, Gene Regulation, and Cognitive Functions of Carboxypeptidase E-Neurotrophic Factor-α1 and Its Variants.

Lan Xiao,Xuyu Yang,Y Peng Loh

doi:10.3389/fnins.2019.00243

Abstract

Carboxypeptidase E, also known as neurotrophic factor-α1 (CPE-NFα1), was first discovered as an exopeptidase and is known to work by cleaving C-terminal basic amino acids from prohormone intermediates to produce mature peptide hormones and neuropeptides in the endocrine and central nervous systems, respectively. CPE-NFα1 also plays a critical role in prohormone sorting and secretory vesicle transportation. Recently, emerging studies have indicated that CPE-NFα1 exerts multiple non-enzymatic physiological roles in maintaining normal central nervous system function and in neurodevelopment. This includes potent neuroprotective and anti-depressant activities, as well as stem cell differentiation functions. In addition, N-terminal truncated variants of CPE-NFα1 have been identified to regulate expression of important neurodevelopmental genes. This mini-review summarizes recent advances in understanding the mechanisms underlying CPE-NFα1’s function in neuroprotection during stress and aspects of neurodevelopment.

Highlights

CPE-NFα1, a member of the M14 metallocarboxypeptidase family was discovered in 1982 in bovine adrenal medulla and named as enkephalin convertase due to its enzymatic activity in processing enkephalin precursor into its mature form (Fricker and Snyder, 1983)
Further demonstration that CPE-NFα1 is a neuroprotective factor in vivo during stress came from studies showing that chronic restraint stress of mice for 1 h/day for 7 days resulted in an increase in CPENFα1 mRNA and protein expression in the hippocampus, with no evidence of neurodegeneration despite increased circulating corticosterone levels under this stress paradigm (Murthy et al, 2013)
In vitro studies showed that incubation of rat cultured hippocampal neurons with CPE-NFα1 enhanced fibroblast growth factor 2 (FGF2) mRNA and protein expression which was inhibited by the Sp1 inhibitor mithramycin A, a transcription inhibitor actinomycin, and ERK inhibitor U0126, suggesting that CPE-NFα1 can upregulate FGF2 via ERK-Sp1 signaling cascade (Cheng et al, 2015)

Summary

Introduction

CPE-NFα1, a member of the M14 metallocarboxypeptidase family was discovered in 1982 in bovine adrenal medulla and named as enkephalin convertase due to its enzymatic activity in processing enkephalin precursor into its mature form (Fricker and Snyder, 1983). Studies on the mechanism underlying the neuroprotective action of CPENFα1 using rat primary hippocampal neurons in culture revealed that when these cells were stressed with H2O2, it activated the ERK and AKT signaling pathways, presumably by binding to a cognate receptor, which up-regulated expression of Bcl2, a pro-survival mitochondrial protein, and down-regulated expression of Caspase 3 to mediate neuroprotection (Cheng et al, 2013) (see Figure 3).

Results

Conclusion